Complications of Alcohol-Related Liver Disease

EXECUTIVE SUMMARY

• Alcoholic liver disease (ALD) can occur when patients consume an average of 30 g to 50 g (between two and four drinks) of ethanol per day for more than five years.
• Patients with liver failure often have impaired gluconeogenesis and are at increased risk for hypoglycemia.
• Start antibiotics early in patients with variceal hemorrhage, even if there is a lack of acute infection. These patients are at high risk for developing infections, such as spontaneous bacterial peritonitis (SBP).
• SBP is diagnosed with a paracentesis showing > 250 cells/µL of polymorphonuclear neutrophils (PMNs). This has a sensitivity of 93% and a specificity of 94%.
• Ethanol withdrawal can occur in patients with ALD who present with complications while actively consuming ethanol.
• Lactulose and rifaximin are the mainstays of management of hepatic encephalopathy.
• Upon diagnosis of SBP, albumin administration in addition to antibiotics decreases the rate of kidney injury in select high-risk patients.

Background

Alcohol, or ethanol, is the most frequently misused drug across the world. It is estimated that, in the United States, 67.3% of the population consumes alcohol, and 7.4% of the population meets diagnostic criteria for substance use disorder.¹ Alcohol use is the leading cause of liver disease and the second most common reason for liver transplantation in the United States.² This article will discuss the complications seen in alcohol-related liver disease.

The Centers for Disease Control and Prevention (CDC) defines an alcoholic drink as 0.5 oz. or 13.7 g of pure ethanol. This amount is equivalent to one 12-oz. beer, 8 oz. of malt liquor, 5 oz. of wine, or 1.5 oz. of 80-proof liquor (hard liquor). The risk of alcohol-related liver disease increases with both the quantity and the duration of intake.

For men, at-risk drinking is the consumption of more than 14 drinks per week or more than four drinks per occasion. For women and in those older than 65 years of age, the amount is more than seven drinks per week or more than three drinks per occasion. In general, 30 g to 50 g (between two and four drinks) of ethanol per day for more than five years can cause alcoholic liver disease.

Of those individuals with long-standing alcohol consumption of more than 60 g per day, 90% will develop hepatic steatosis.³ Additionally, 30% of individuals with long-standing consumption of at least 40 g of ethanol per day will develop cirrhosis.³

Definition

Alcoholic liver disease (ALD) is a spectrum of disorders that range from fatty liver to the development of cirrhosis, all related to the consumption of ethanol.³ The spectrum of ALD is categorized by the histologic changes to the liver parenchyma. This often is a diagnosis of exclusion and has no unique diagnostic tests.

The differential diagnosis of ALD includes non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH); Reye syndrome; viral hepatitis, drug-induced hepatitis, autoimmune hepatitis; fulminant Wilson’s disease; ascending cholangitis; and hepatocellular carcinoma (HCC).

As noted, the amount and frequency of ethanol used play a role in the development of ALD, with the quantity and duration being the highest risk factors. Women are more susceptible than men. Obesity and a high-fat diet also increase the risk of developing ALD, but a variety of metabolic, genetic, environmental, and immunological factors also play a role.

Concurrent hepatitis C infection is associated with a younger age of onset for ALD, more advanced histological damage on presentation, and decreased overall survival. A protein called patatin-like phospholipase domain-containing-protein 3 (PNPLAP3) is associated with the development of cirrhosis.³

Pathophysiology

Ethanol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase. With altered redox inside the cell, nicotinamide adenine dinucleotide (NAD) is reduced to nicotinamide adenine dinucleotide plus hydrogen (NADH), leading to the formation of glycerol phosphate. Glycerol phosphate combines with fatty acids to form triglycerides, which accumulate in the liver. Interleukins (IL) and neutrophils attack the hepatocytes, causing swelling and alcoholic hepatitis. Subsequently, ongoing liver injury leads to irreversible liver damage, or cirrhosis. These stages are not necessarily progressive, and there can be significant overlap.

Hepatic Steatosis (Alcoholic Fatty Liver)

Hepatic steatosis is the accumulation of small fat droplets within the liver cells, around the venules, and approaching the portal tracts due to this altered redox potential in these locations.³ Hepatic steatosis can develop due to alcohol use resulting in alcoholic fatty liver, or as a result of metabolic derangements, such as diabetes, obesity, or hyperlipidemia, a condition termed nonalcoholic fatty liver disease. At this stage, the condition is reversible. If unchecked, up to 20% of cases of hepatic steatosis progress to cirrhosis.⁴

Alcoholic Hepatitis

Alcoholic hepatitis (AH) is a syndrome of liver inflammation in the setting of heavy ethanol use (often more than 100 g/day). This acute inflammation can progress rapidly to liver failure. It is divided into mild-moderate and severe based on the Model for End-Stage Liver Disease (MELD) score and the MELD-Na score. The MELD and MELD-Na scores predict 90-day mortality. The Maddrey’s discriminating function (DF) is a useful predictive tool for the 30-day mortality in AH; DF scores > 32 have a 35% to 45% 30-day mortality. (See Table 1.)

The histopathology of AH consists of the formation of eosinophilic fibrillar material (known as Mallory hyaline or Mallory-Denk bodies) within swollen hepatocytes. Lobular infiltration of polymorphonuclear leukocytes (neutrophils) also is abundantly present. It is thought that 10% to 20% of cases of AH are likely to progress to cirrhosis annually, while 10% will have regression with alcohol abstinence.³

Presentation

The typical age of AH presentation is between 40 and 50 years of age. Patients present with rapid onset of jaundice, fever, tender hepatomegaly, ascites, and proximal muscle loss. They also might have signs of encephalopathy. Rarely, patients can present with the hepatorenal syndrome — one of the leading causes of death.

Diagnosis

The diagnosis of AH requires a clinical history consistent with alcohol use and exclusion of alternative etiology for hepatitis. In the emergency department (ED), the laboratory workup must include a complete blood count (CBC), liver function tests (LFTs), prothrombin time/international normalized ratio (PT/INR), and a basic metabolic panel (BMP). Testing for viral hepatitis will help admitting teams and primary care clinicians exclude the presence of viral hepatitis. Serum ammonia will be elevated in patients when AH is the etiology of their encephalopathy.

In patients with new ascites due to AH, a paracentesis, though not emergent unless an infection is suspected, will show a serum ascites albumin gradient (SAAG) > 1.1. For diagnostic imaging, a liver ultrasound will help exclude other considerations on the differential diagnosis. Ultimately, a liver biopsy might help when the diagnosis is uncertain.

Management

Patients with AH must be given resources and encouraged to abstain from alcohol. Acutely, these patients should be monitored closely for the development of acute alcohol withdrawal, which should be treated. The management of acute alcohol withdrawal is beyond the scope of this article but includes the use of benzodiazepines and barbiturates, along with supportive management.^5,6 Nutritional support and the identification and treatment of any infections or other co-existing liver diseases also are important in the management of AH.³ With any liver diseases, the use of acetaminophen must be limited to no more than 2 g/day.

Steroids (prednisolone) and pentoxifylline both have been used in the management of AH, but the STOPAH trial did not find any statistically significant mortality reduction.¹² The tumor necrosis factor (TNF) antagonists infliximab and etanercept also have been tried with no clinical benefit and, in the case of etanercept, worse patient outcomes.¹³

Ultimately, for those with severe AH who do not respond to medical management, liver transplantation can be a consideration.^2,14

Cirrhosis

Cirrhosis, or chronic liver disease (CLD), affects 3.6 out of every 1,000 adults in North America and is responsible for more than 1 million days of work loss and 32,000 deaths annually.¹⁵ Alcoholic cirrhosis is the irreversible end-stage result of liver damage on the spectrum of ALD.¹⁶ Excessive alcohol intake results in liver fibrosis and nodule formation, which lead to portal hypertension. This results in impaired liver function, altered patient hemodynamics, and a host of immunologic changes.¹⁷ Additionally, with synthetic liver dysfunction, a series of neurotoxins accumulate, the most clinically important of them being ammonia. Liver dysfunction also leads to altered neurotransmission and astrocyte edema. A disrupted blood-brain barrier also is seen in CLD.¹⁸

Patients with cirrhosis have significant increased mortality, with an estimated five-year mortality rate of well-compensated cirrhosis of 58%.¹⁹ It is important to differentiate a patient with compensated vs. decompensated cirrhosis. Patients with compensated cirrhosis lack major complications from the disease process and generally are asymptomatic. This is in comparison to those with decompensated cirrhosis, who are actively experiencing complications and symptoms from the disease, such as encephalopathy, worsening ascites, spontaneous bacterial peritonitis (SBP), or gastrointestinal bleeding (GIB).¹⁷ There is a 10-fold increase in mortality in cirrhotic patients who are decompensated, compared to a five-fold increase in mortality in compensated patients when compared to the standard population.¹⁷

Presentation

Patients with compensated cirrhosis often are asymptomatic, while decompensated alcoholic cirrhosis presents with complications that necessitate prompt recognition to prevent further decompensation. Signs of decompensated cirrhosis include worsening jaundice, scleral icterus, and signs of volume overload with shortness of breath or swelling in the abdomen, lower extremities, or with anasarca (see following section). More serious symptoms include variceal bleeding resulting in hematemesis, melena, rectal bleeding, and hemorrhagic shock.

Patients also can present with sleepiness, personality changes, or altered mental status, all indicative of hepatic encephalopathy (HE) (see following section).¹⁸ Infection also can precipitate CLD decompensation. Symptoms including fever, nausea, vomiting, and decreased oral intake are among a few possible presenting symptoms. In addition to fever, more specific signs of infection, such as urinary symptoms, cough and sputum, or alterations in mental status, are possible presentations as well.¹⁷ These infections are a result of the weakening of the immune system that takes place in a decompensated state and are the most common cause for mortality in cirrhosis.¹⁷

Diagnosis

The physical examination findings of cirrhosis are both manifestations of the disease itself as well as complications from the disease. Common findings include abdominal distension and ascites, palmar erythema, caput medusae, spider angioma, gynecomastia, atrophy of muscles, jaundice and scleral icterus, asterixis, and altered mental status.

Laboratory studies are a critical part of evaluating alcoholic cirrhosis in the ED. They can help determine if cirrhosis is present, if there is decompensation of the cirrhosis, and if alcohol is a possible contributor. The CBC can help assess for leukocytosis, low hemoglobin, and the thrombocytopenia that often accompanies cirrhosis; the BMP allows for evaluation of the creatinine and electrolytes. In patients with alcoholic cirrhosis, the liver is injured, and its function is compromised. The liver enzymes, such as aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), can be used to evaluate the degree of injury. The INR, partial thromboplastin time (PTT), albumin, and total bilirubin help assess the status of the liver function.²⁰

Moderate elevations in liver enzymes (five to 10 times normal) and a 2:1 elevated ratio of AST:ALT are suggestive of alcoholic disease and cirrhosis. It is important also to check a glucose level and lactate level, since these patients are at risk for hypoglycemia secondary to impaired gluconeogenesis and hypoperfusion secondary to intravascular depletion. When appropriate, consider other causes of cirrhosis and acute liver failure by performing viral hepatitis panels and serum acetaminophen levels.²⁰

In a new diagnosis of cirrhosis, an ultrasound (US) with Doppler often is beneficial for definitive diagnosis. Ultrasound is widely available and noninvasive. On US, the liver is atrophic, irregular, nodular, and has increased echogenicity. On Doppler, there is decreased portal blood flow. Ascites, when present, also can be detected.²⁰ Otherwise, imaging in the ED generally is guided by the presenting symptoms. Additional imaging, such as chest X-ray for a cough or computed tomography (CT) of the abdomen and pelvis for abdominal pain, may help exclude other diagnoses, such as infection, which can be causing patients to progress into decompensated cirrhosis.

Management

When evaluating a patient with alcoholic cirrhosis in the ED, the basic tenets of resuscitation apply, since these patients can decompensate rapidly because of a tenuous circulatory and volume status.¹⁷ Subsequently, the focus is to manage CLD complications. ED interventions are tailored to the complication a patient is experiencing and might include fluid and blood product resuscitation. In general, patients with sepsis and CLD need more fluids than patients without cirrhosis, earlier use of albumin, earlier use of vasopressors, and early assessment of the adequacy of resuscitation using ultrasonography.²¹

Early airway management might be needed in massive variceal bleeds or with grade 4 encephalopathy. The patient with volume overload will need diuresis. All unstable or tenuous patients should have two large bore intravenous (IV) lines placed and maintained. These patients all should be admitted to an intensive care unit (ICU). Transfer to an ED with gastroenterology services or transplant capabilities should be considered if not available at the site where a patient first presents. Transplant candidacy can be assessed by using the MELD-Na score, in conjunction with transplant specialists. (See Table 1.)

If a patient with known cirrhosis is evaluated and found to be well-compensated and well-appearing, they can be discharged with close outpatient follow-up. Primary care as well as gastroenterology (GI) follow-up should be arranged.

Portal Hypertension and Varices

Among patients with cirrhosis, almost 90% will go on to develop portal hypertension.²² One study showed that almost half of the patients who are newly diagnosed with cirrhosis will already have gastroesophageal varices.²³ As a result of portal hypertension, gastroesophageal varices can develop and ultimately rupture, resulting in upper gastrointestinal bleeding (UGIB). Rupture of these varices is found to be among the most common of fatal complications of cirrhosis and necessitates early recognition and treatment.²² The six-week mortality rate after an episode of variceal bleeding is between 15% and 20% and is as high as 30% in those with severely decompensated cirrhosis.²⁴

Presentation

Cirrhotic patients presenting with a UGIB should raise suspicion for a variceal bleed, although varices typically are diagnosed via endoscopy. Duplex Doppler ultrasound or more invasive studies may be done to diagnose the varices, but these rarely are performed in the ED.²⁵

Bleeding may be identified as emesis that is bright red, has clots, or appears like coffee grounds, as well as bowel movements with melena. Patients with bleeding esophageal varices may present with slow bleeds, stable vitals, and stable blood counts. They also may present on the other end of the spectrum with massive bleeds resulting in hemorrhagic shock. Laboratory tests specific to evaluating and treating variceal bleeding, including a CBC, BMP, type and screen, and coagulation tests such as PT/INR and PTT, should be obtained.

Management

The ED management of bleeding esophageal varices is guided by the severity of the presentation. If a patient is presenting altered, somnolent, or with active hematemesis, there may be an acute need for airway protection. In these cases, patients should be intubated with subsequent nasogastric (NG) tube placement. These patients also will require aggressive resuscitation using primarily blood products, using two large bore IVs.

A restrictive transfusion strategy, with a goal target hemoglobin of 7 g/dL to 9 g/dL, provides better survival in CLD patients compared to a typical liberal transfusion strategy.²⁶ Crystalloids may be used as a temporizing measure while blood products are being ordered, but consideration must be taken to prevent hemodilution, worsening coagulopathy, or resulting acute kidney injury. There is no evidence to support aggressive correction of either coagulopathy or thrombocytopenia.^27,28

Ultimately, these patients likely will require endoscopy for definitive management of variceal bleeding. The timing of this depends on the patient’s clinical status, but the current Baveno VI Consensus Guidelines recommend that endoscopy be performed within 12 hours of presentation.²⁸

In terms of medication administration, octreotide (50 mcg bolus and 50 mcg/h IV) and vasopressin (0.2 units/min IV and increase by 0.2 units/min as needed, with a maximum rate of 0.8 units/min) are mainstays. Outside the United States, terlipressin (triglycyllysine vasopressin) is the most commonly recommended drug. These medications result in splanchnic vasoconstriction, decreasing blood flow to the portal vein and, subsequently, the pressure inside the variceal vessel.

Bacterial infections are found in 35% to 66% of patients with bleeding varices and are a significant risk factor for early rebleeding and development of spontaneous bacterial peritonitis. Given this, antibiotics such as ceftriaxone, 1 g IV every 24 hours, or, if necessary, quinolones (ciprofloxacin 400 mg IV every 12 hours or ofloxacin 400 mg orally [PO] every 12 hours) should be started as soon as possible.²⁹

There is a significant reduction in not only bacterial infections but also mortality and length of hospital stay with antibiotic administration in cirrhotic patients with variceal bleeds.³⁰ The number needed to treat (NNT) for infectious complication prevention is one in four; for death prevention, the NNT is one in 22.³¹

Other medications to consider include a proton pump inhibitor (PPI), such as pantoprazole (40 mg IV q8h), and pre-endoscopy doses of GI motility agents, such as metoclopramide and erythromycin (250 mg IV; do not use in QT prolongation). While these medications do not necessarily offer a clear mortality benefit, endoscopists sometimes prefer these to be started as soon as possible to provide improved visualization during endoscopy.

All patients with a suspected or confirmed acute variceal bleeding must be admitted to an ICU or other closely monitored unit.

A feared complication of bleeding esophageal varices is massive hemorrhage. In these cases, endoscopy is needed emergently. When endoscopy is delayed or not immediately available, placement of a Sengstaken-Blakemore tube or Minnesota tube should be considered. These devices are only a temporizing measure to provide pressure at the site of bleeding, and definitive management still is required. The use of these devices is not supported by high-quality evidence.^28,32,33

After a patient is intubated, the device can be inserted into the esophagus and stomach, where a balloon is located at each site. The balloons then are inflated to tamponade the bleeding vessels. Insertion of this device is rare in the ED but is a critically important skill. The critical steps of the procedure should be reviewed by ED clinicians regularly, along with knowledge of the type of device stocked and its location within the facility.

Ascites

Ascites is defined as fluid accumulation within the peritoneal cavity. Ascites most commonly is caused by cirrhosis; however, other etiologies include malignancy, heart failure, and kidney failure. In patients with cirrhosis, ascites develops due to progressive portal hypertension and increasing fluid retention because of alterations in sodium reabsorption.³⁴

The development of ascites is one of the markers for progression of cirrhosis from a compensated to a decompensated state, occurring in about 50% of CLD patients within 10 years of the diagnosis. In addition to weight gain, discomfort, and dyspnea, this disease process also can result in life-threatening complications, such as spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome.³⁵

At low volumes, ascites may present with vague abdominal discomfort and early satiety, along with the classic stigmata of cirrhosis and CLD mentioned previously in this article. As it progresses, ascites can result in weight gain, abdominal distension, and in the case of tense ascites, patients may begin to experience significant discomfort and respiratory distress.³⁵

The diagnosis of large-volume ascites is clinical. Definitive identification and quantification of ascites can be performed through ultrasound or CT imaging. All patients with new ascites should have a paracentesis to determine the etiology of ascites, and those for which there is concern for SBP always require an emergent diagnostic paracentesis.^34,36

Ascitic fluid analysis includes color, consistency, cell count and differential, albumin, total protein, Gram stain, and fluid culture.^34,37 The protein and SAAG will allow for confirmation of the source of ascites. The SAAG is calculated by subtracting the ascitic fluid albumin from the serum albumin, and a SAAG > 1.1 g/dL supports a diagnosis of portal hypertension as the source of ascites.³⁸ Ascitic total protein of < 2.5 g/dL also supports a diagnosis of cirrhosis as the source of ascites.³⁴ This low protein ascites is due to the decreased permeability of a cirrhotic and fibrosed liver.³⁴

Additionally, blood tests, including liver function tests, PT/INR, and serum albumin, all will be helpful in identification of cirrhosis as the source of ascites. When SBP is suspected, urine and blood cultures should be drawn as well.

Management

The mainstay of treatment of ascites includes the use of diuretics, modest dietary sodium restriction, and large-volume paracentesis if needed. More extreme measures, such as the transjugular intrahepatic portosystemic shunt (TIPSS) procedure and transplantation, are used on a case-by-case basis for a narrow range of appropriate patients.³⁴ Table 2 describes the different medications and interventions used to manage ascites.

Spironolactone, a mineralocorticoid receptor blocker, is the foundation of ascites management. While it often is used as a single agent, patients requiring a more rapid resolution of ascites may use dual therapy with furosemide as well. Patients with diuretic management of ascites should be monitored closely for complications, including intravascular volume depletion, hepatic encephalopathy, renal impairment, or electrolyte derangements.³⁴

Historically, strict sodium restriction was encouraged for patients with ascites; however, those with strict sodium restrictions were found to have increased complication rates.³⁴ A moderate sodium restriction between 5 g to 7 g is the current recommendation, with a focus on maintaining the patient’s muscle mass and avoiding sarcopenia.³⁹

The standard of care for patients with large-volume ascites is a large-volume paracentesis (LVP), which will remove fluid in a more predictable and reliable way when compared to diuretics alone.^34,39 The LVP should have the goal of removing as much fluid as possible during a single session. Importantly, patients undergoing LVP of 5 L or more should receive volume repletion with 8 g of albumin for every liter of ascitic fluid removed, to prevent the risk of subsequent development of renal failure, hypovolemia, and hyponatremia.^34,39 LVP is, at times, performed in the ED, but generally this should be performed as an inpatient, in a procedure center, or in a dedicated specialty clinic.

The TIPSS procedure has been shown to better control refractory ascites and improve a patient’s quality of life. However, only a select patient population is appropriate for this procedure, and there are significant risks without consistent improvement in survival. A TIPSS creates an artificial connection between the portal and hepatic veins, which decompresses the portal system and decreases ascites development.³⁴ TIPSS is not an ED procedure, but ED providers should be aware of this procedure and the resultant changes in patient physiology.

Spontaneous Bacterial Peritonitis

SBP is defined as the development of bacterial infection within ascites in the absence of an intra-abdominal source of infection. It is a feared complication for those with ascites. The majority of SBP is caused by gram-negative aerobic bacteria, with Klebsiella pneumoniae and Escherichiae coli being the most common culprits. Streptococcus pneumoniae and Streptococcus viridans are the most common gram-positive pathogens.³⁷ SBP is thought to be due to translocation of gut bacteria.³⁶

Despite advances in identification and treatment of SBP, it continues to carry a high mortality rate of about 20%, and a one-year survival between 30% and 50% after the first episode of SBP.³⁴ Patients with cirrhosis presenting with ascites and acute onset abdominal pain, a temperature of > 100°F, altered mental status, worsening encephalopathy, declining renal function, and any infectious signs and symptoms require prompt evaluation for SBP through a diagnostic paracentesis.^36,37

A diagnostic paracentesis allows for evaluation of ascitic fluid cell count, Gram stain, and culture. A polymorphic neutrophil count > 250 cells/µL without an identifiable surgical source of nidus is diagnostic for SBP and has a sensitivity of 93% and a specificity of 94%.³⁷ The addition of a Gram stain and culture allows for identification of the causative organism while also allowing for further tailoring of treatment.³⁴

Early antibiotics are critical to the treatment of SBP. Third-generation cephalosporins, such as ceftriaxone 1 g IV daily, are recommended for SBP treatment. If SBP is thought to be nosocomial, piperacillin/tazobactam 4.5 g IV three times per day can be considered until a pathogen is identified.

Renal failure is the most common cause of death in patients with SBP. Albumin therapy (1.5 g/kg given within six hours of SBP detection and another 1 g/kg dose on day 3) has been shown to significantly decrease the development of renal dysfunction in CLD patients with SBP who have a creatinine that is rising or that is > 1 mg/dL, or a blood urea nitrogen (BUN) > 30 mg/dL, or a bilirubin > 4 mg/dL.³⁴

Patients with a prior history of SBP should be considered for secondary prophylaxis with a fluoroquinolone or trimethoprim-sulfamethoxazole (TMP-SMX) to prevent a recurrence. Primary antibiotic prophylaxis is indicated for patients with ascitic fluid with a protein < 1.5 g/dL; renal impairment with creatinine > 1.2 mg/dL; BUN > 25 mg/dL; or decompensated cirrhosis. Antibiotics used for primary and secondary prophylaxis include a fluoroquinolone (such as norfloxacin 400 mg daily or ciprofloxacin 500 mg daily) or TMP-SMX (800 mg sulfamethoxazole/160 mg trimethoprim daily).³⁹

Paracentesis

A paracentesis is a procedure performed to sample and remove free fluid from within the peritoneal cavity. A diagnostic paracentesis can be performed in the ED to remove a small sample of ascitic fluid for rapid testing and identification of the source of ascites, or, more importantly, to diagnose SBP.⁴⁰

An LVP, defined as removal of > 10 mL/kg of ascites, is used to remove large volumes of ascitic fluid for diagnostic and therapeutic reasons in patients with tense ascites. In general, LVP is not an emergency medicine procedure because of the time and resources required to complete the procedure. Patients undergoing LVP typically have immediate relief as the ascites is removed from their peritoneal space.

While medical management, as discussed earlier, helps to prevent recurrence, some patients will require frequent LVP. The frequency of LVP is determined by an individual’s rate of accumulation of ascites, which is determined by their ability to tolerate diuretics, compliance with medication and diet recommendations, renal function, and tolerance of abdominal distension.⁴¹

The most common complication of LVP is persistent ascitic fluid leak, while more significant complications, such as bleeding and perforation of vessels and viscera, are rare and have decreased with the use of ultrasound guidance. As fluids shift during LVP, there is a risk of paracentesis-induced circulatory dysfunction (PICD), which presents as hypovolemia, hyponatremia, and renal injury.⁴¹ Because of increased risk of PICD with increased volume of ascitic fluid removed, it is recommended to give an albumin infusion of 8 g for every liter of ascites removed when removing > 5 L of fluid.^34,39,41

Paracentesis must be done in a sterile manner and using ultrasound guidance when accessible. While historically paracentesis was done with a landmark technique, the use of ultrasound increased success, decreased complication rates, and reduced procedure completion time, and should be used whenever available.^34,42 The only absolute contraindication to a paracentesis is disseminated intravascular coagulation. Please refer to the New England Journal of Medicine procedure video for the specific steps of a paracentesis.⁴² (https://www.nejm.org/doi/full/10.1056/NEJMvcm062234)

Hepatic Encephalopathy

Hepatic encephalopathy (HE) is defined as brain dysfunction due to liver insufficiency and/or portosystemic shunts that manifests as a wide spectrum of neurologic or psychiatric abnormalities.^43,44 Despite the difficulty with diagnosis and sometimes subtle symptoms, HE is thought to be the most frequent complication of cirrhosis, with a 25% risk of development within the first five years of cirrhosis diagnosis.⁴⁴

There are a wide range of presentations for those experiencing HE, and symptoms may wax and wane. Symptoms are somewhat reversible; however, recent studies have expressed concern for lingering subtle cognitive dysfunction in these patients.⁴⁵ Patients with overt HE will present with cognitive dysfunction and abnormal behaviors that range from agitation to lethargy, all the way to confusion and coma. Patients often will experience inverted sleep-wake cycles and disorientation, and often have the characteristic physical exam finding of asterixis.

Minimal HE is an increasingly recognized condition in the spectrum of HE. These patients often are harder to diagnose because of the more subtle changes in cognition that may only be recognized by caregivers, close family, or with more nuanced neuropsychiatric testing. Despite the subtle symptoms, minimal HE still is noted to negatively affect patients’ quality of life.⁴⁵

The diagnosis of HE entails the presence of cirrhosis, the exclusion of other etiology of altered consciousness, and a physical examination consistent with the symptoms previously mentioned. Blood ammonia levels often are elevated, but their role in the diagnosis of HE is poorly substantiated. A normal serum ammonia does not exclude HE, an elevated level does not make the diagnosis, and the level does not correlate with the degree of encephalopathy.^43,45 Additional imaging, such as a brain CT or magnetic resonance imaging (MRI) and an electroencephalogram (EEG), may be pursued but has limited utility in the ED.⁴³

The severity of HE is graded most commonly using the West Haven Criteria (see Table 3), which assess based on the degree of dysfunction and symptoms. There is increasing severity of symptomatology with increasing grading of the HE, ranging from subtle changes in attention span and sleep-wake cycle to gross disorientation, behavior disturbance, and, finally, coma.^42-40

The pathophysiology of HE is multifactorial and incompletely understood. Ammonia is thought to be a key component, which when in excess, crosses the blood-brain barrier. This results in central nervous system (CNS) inflammation and derangements in energy metabolism, neurotransmission, and communication between cells.¹⁸ Additionally, it is increasingly recognized that other neurotoxins, such as manganese, and gut microbiome dysbiosis also play a role in the complex presentation of HE.^44,45

In patients presenting with progressive HE, there should be extensive evaluation for the etiology of decompensation. The most common reason for the development of HE is a GI bleed. Other common triggers for HE range from simple causes, such as medication non-compliance, constipation, dehydration, and alcohol use, to more sinister etiologies, such as infection and renal failure. Medications also are implicated in triggering HE, including benzodiazepines, sedatives, analgesics, diuretics, and proton pump inhibitors.^18,43,45 Finally, about 35% of those patients who have undergone a TIPSS procedure will experience HE, and a high level of suspicion should be maintained for these patients.⁴³

Management of HE should focus on treatment of its precipitating factors, treatment of the acute encephalopathy, and the prevention of further episodes of HE. The ultimate treatment for HE is liver transplantation; however, this is only available to a select set of patients.

Nonabsorbable disaccharides, most commonly lactulose (15 mL to 30 mL PO two to four times per day, aiming for multiple loose bowel movements; or 300 mL in 700 mL of water as a retention enema), is the mainstay in treatment of HE. Lactulose decreases ammonia absorption by inducing a more rapid gut transit time, reducing ammonia-producing bacteria, and altering the gut pH to reduce the amount of the absorbable form of ammonia.¹⁸ Lactulose currently is used in the treatment of acute HE, as primary prophylaxis in those with GI bleeds, and as secondary prophylaxis in those with CLD.

Rifaximin (550 mg PO BID), a poorly absorbed broad-spectrum antibiotic, also is used with the aim to decrease the amount of ammonia absorbed by reducing ammonia-producing bacteria in the gut.⁴⁶ Lactulose and rifaximin commonly are used in conjunction with each other and may improve the rate of resolution of HE. They also are used together for secondary prophylaxis as well.^18,43

Other treatment options, such as probiotics, branched chain amino acids (valine, leucine, isoleucine), L-ornithine L-aspartate (or LOLA), antioxidants, and albumin infusions, all have limited evidence and are not universally recommended at this time, but they should be considered in consultation with a gastroenterologist or hepatologist.^18,43,44

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is the onset of renal failure in the setting of advanced CLD. It is a diagnosis of exclusion. Patients present with a rapid rise in creatinine accompanied by a low sodium excretion rate, oliguria, a benign urine sediment, and the absence of proteinuria.

There are two distinct types. Type 1 has a two times rise in creatinine in less than two weeks and is the more severe type. Type 2 has a slower onset and a slightly better prognosis.

The treatment for HRS includes norepinephrine and albumin in the critically ill, and midodrine, octreotide, and albumin in the non-critically ill patients. All of these patients need admission. Ultimately, these patients need a liver transplant.

Hepatopulmonary Syndrome

Hepatopulmonary syndrome is defined as hypoxemia due to dilated pulmonary vasculature in the setting of CLD and portal hypertension. The mechanism is not completely understood, but it is thought to be caused by excess nitric oxide production. This results in an elevated alveolar-arterial oxygen gradient.

These patients present with shortness of breath and hypoxemia, which tend to worsen when the patient goes from the supine to the upright position. Hypoxemia is treated with supplemental oxygen, but the definitive treatment requires a liver transplant.⁴⁷

Other Complications

There are additional complications that patients with cirrhosis may face because of their altered physiology.

Hepatic hydrothorax is a pleural effusion that develops from the passage of ascitic fluid through a defect in the diaphragm due to increased abdominal pressures. Patients with this condition are at risk for developing spontaneous empyemas.⁴⁸

Porto-pulmonary hypertension is a severe type of pulmonary hypertension due to portal hypertension that can result in right heart failure.⁴⁹

Cirrhotic cardiomyopathy is cardiac dysfunction and cardiomyopathy due to the pro-inflammatory state during cirrhosis as well as abnormal hemodynamics of the cirrhotic patient.⁵⁰

Portal hypertensive gastropathy results in irritation in the lining of the stomach, with resultant bleeding. This is another common cause of hematemesis and UGIB in the cirrhotic patient.⁵¹

Portal vein thrombosis is a blood clot in the portal vein, which can cause acute abdominal discomfort, increased venous pressure, the development of variceal veins, and acute intestinal ischemia.⁵²

Patients with cirrhosis are at an increased risk of developing hepatocellular carcinoma (HCC). Currently, screening ultrasounds are recommended every six months.⁵³

Disposition

ED disposition for these patients will depend on their current condition. Patients with newly diagnosed hepatic steatosis or well-compensated cirrhosis with stable vital signs often can go home with close outpatient follow-up. Those with decompensated cirrhosis will need further evaluation of the trigger of their decompensation and management of their acute symptoms. Often, they require inpatient admission.

Patients with overt hepatic encephalopathy and variceal bleeds will need a higher level of care, including gastroenterology consultation, emergent endoscopy, and possible ICU admission. The majority of hemodynamically stable patients with decompensated cirrhosis, including those with SBP and ascites, will be admitted to medical-surgical wards for management of their acute pathologies.

Conclusions

Excessive, chronic alcohol intake is common in the United States and worldwide, and results in progressive liver damage and dysfunction. Alcoholic hepatitis and hepatic steatosis are conditions in which liver injury still is reversible with cessation of alcohol use, while cirrhosis is irreversible end-stage progression of chronic liver disease and has a high morbidity and mortality.

Complications of ALD and cirrhosis include portal hypertension resulting in ascites accumulation, hepatic encephalopathy, variceal bleeding, and life-threatening infections, such as spontaneous bacterial peritonitis.

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