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Alcoholic Liver Disease: Implications for the Advanced Practice Provider
The Journal for Nurse Practitioners 15 (2019) 506e510
Contents lists available at ScienceDirect
The Journal for Nurse Practitioners journal homepage: www.npjournal.org
Alcoholic Liver Disease: Implications for the Advanced Practice Provider Hender Rojas, MSN, ACNP-BC a b s t r a c t Keywords: alcoholic hepatitis alcoholic liver disease alcohol use disorder alcohol withdrawal syndrome liver transplantation
Alcoholic liver disease is a largely preventable condition that contributes to mortality in the United States and worldwide. This article discusses the pathogenesis, risk factors, diagnosis, screening tools, clinical presentation, and predictors of mortality. Medical management using the most recent clinical guidelines from the 2018 American College of Gastroenterology and the American Gastroenterological Association Institute are reviewed. Supportive care, abstinence promotion, cognitive behavioral therapy, nutritional needs, pharmacotherapy, alcohol withdrawal management, intensive care, and liver transplantation are discussed, as well as future research directions. Finally, practice implications to better address this population’s needs using a multidisciplinary approach are addressed. © 2019 Elsevier Inc. All rights reserved.
Alcohol abuse is 1 of the main causes of preventable liverrelated disease that contributes to mortality in the United States and worldwide. Alcohol is a psychoactive substance that can cause dependence. The unhealthy use of alcohol burdens communities with disease and social and economic stress. The amount and pattern of alcohol use have a direct relation to its harmful properties.1 The causes of liver disease vary across the world. For example, in Asia and Africa, viral hepatitis is the driving factor, whereas in North America and Europe, it is primarily attributed to alcohol abuse.2 According to the World Health Organization, alcohol abuse causes over 200 disease conditions, including dependence on alcohol, cirrhosis, and cancers, as well as injuries. Furthermore, in 2012, about 3.3 million deaths, or 5.9% of all global deaths, were related to the consumption of alcohol.1 Estimations done by the Centers for Disease Control and Prevention in 2010 put the price of excessive alcohol consumption in the US at $249 billion, mainly related to losses in workplace productivity (72% of the total cost), health care costs, and a combination of criminal justice, motor vehicle crash, and property damage expenses.3 The National Institute of Alcoholism and Alcohol Abuse defines alcohol use disorder (AUD) as the consumption of > 3 drinks per day in males and > 2 drinks per day in females for > 5 years and binge drinking as the consumption of > 5 drinks in males and > 4 drinks in females within a 2-hour period. By these definitions, about 1 in 12 adults have AUD. In the US, 1 drink is quantified as a beverage holding about 14 g alcohol (12 oz beer, 5 oz wine, or 1.5 oz hard liquor).4 https://doi.org/10.1016/j.nurpra.2019.04.002 1555-4155/© 2019 Elsevier Inc. All rights reserved.
The care of these patients requires a multidisciplinary approach. It is crucial that advanced practice providers (APPs) are wellinformed about this disease process as they are likely to be involved in the care of these patients in both primary and acute care practice settings. This article discusses pathogenesis, risk factors, diagnosis, screening tools for alcohol abuse, clinical presentation, and predictors of mortality that are associated with alcoholic liver disease (ALD). Medical management using the most recent clinical guidelines from the American College of Gastroenterology for the management of ALD (2018) and the evidence-based clinical practice updates from the expert review from the Clinical Practice Updates Committee of the American Gastroenterological Association Institute (2017) for severe acute alcoholic hepatitis are discussed. Supportive care, abstinence promotion, cognitive behavioral therapy, nutritional needs, pharmacotherapy, alcohol withdrawal management, intensive care, and liver transplantation (LT) are reviewed. Research and future directions for treatment and management are considered. Finally, practice implications for the APP to better address this population’s needs using a multidisciplinary approach are discussed. Pathogenesis: Natural Progression From Steatosis to Cirrhosis ALD encompasses a spectrum of liver pathology. Initially, fatty liver changes are generally asymptomatic but evident in the great majority of heavy alcohol drinkers. These hepatic changes can be generally reversed once alcohol use is discontinued. Alcohol use can be a contributing factor in accelerating hepatic fibrosis in patients who may also have other types of liver disease, such as
H. Rojas / The Journal for Nurse Practitioners 15 (2019) 506e510
hepatitis C virus (HCV).4 Up to 20% to 40% of alcoholics develop fibrosis, and 10% to 20% eventually progress to cirrhosis. Furthermore, 1% to 2% of patients with cirrhosis are diagnosed with hepatocellular carcinoma annually.5 Hepatic-related complications as a result of cirrhosis include portal hypertension, spontaneous bacterial peritonitis, ascites, hepatic encephalopathy, variceal bleeding, hydrothorax, hepatopulmonary syndrome, and hepatorenal syndrome. Alcoholic hepatitis (AH) can be found in patients with advanced fibrosis or established cirrhosis with concurrent heavy use of alcohol. Patients with AH will present with hepatic complications, jaundice, and a sharp increase in serum bilirubin. AH patients’ short-term mortality rate can be very high, up to 30% to 50% at 3 months.2
Risk Factors: Disease Modifiers and Cofactors According to Singal et al, approximately 10% to 20% of patients with ongoing alcohol abuse progress to advanced liver disease and cirrhosis. Behavioral, environmental, and genetic factors may possibly play a role as contributing factors and disease modifiers.4 Sex differences account for variance when comparing the amount of alcohol use and developing ALD. For example, females, who are more likely to have a high body fat content as well as lower gastric alcohol dehydrogenase activity, are more at risk for ALD with lower amounts of daily alcohol use.4 Environmental risk factors are significant in disease progression to cirrhosis; for example, obesity coupled with heavy alcohol use doubles the likelihood of individuals progressing to cirrhosis.2 Cigarette smoking, elevated iron levels, and having concurrent hepatitis B or HCV infection increases the risk of liver injury, cirrhosis, hepatic decompensation, and hepatocellular carcinoma.4 On the other hand, the consumption of coffee has been shown to have protective properties against alcoholinduced liver injury when 4 or more cups are consumed per day; coffee drinkers have a lower risk of advancing to cirrhosis versus those who are not coffee drinkers.6 Genetic factors such as modifiers of neurotransmission (gamma-aminobutyric) and alcohol metabolism (alcoholic dehydrogenase and acetaldehyde dehydrogenase enzymes) may decrease the threshold to resist alcohol consumption or may enhance susceptibility in those who already have AUD to further progress to ALD. Several large studies have shown that the principal genetic patatinlike phospholipase domain containing protein 3 (PNPLA3), could be the primary factor that decisively affects the risk and severity of ALD.4
Diagnosis ALD in the early clinical stages has minimal or no symptoms in most patients, as well as in those who have compensated cirrhosis. Therefore, diagnosis in this setting relies on clinical suspicion, documentation of excessive alcohol consumption, laboratory findings, imaging, and, if needed, a liver biopsy. The clinician needs to be cognizant that self-reports of alcohol use frequently downplay the actual consumption pattern and quantity; if appropriate, relatives and friends may provide useful information. Suspicion for AUD diagnosis is confirmed when excessive alcohol consumption (> 40-50 g/d) is documented, along with abnormal clinical and/or biological findings pointing toward liver injury.6 Box 1 discusses screening tools for alcohol abuse.
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Box 1. Screening Tools for Alcohol Use7 The CAGE questionnaire is a 4-question test with binary answers; 2 “yes” responses are considered a positive test eliciting additional testing. The Alcohol Use Disorders Inventory Test consists of 10 questions with 5 possible answers and a focus on the identification of heavy drinkers. A single screening question “How many times in the past year have you had 5 drinks (males) or 4 drinks (females) or more in a day?” may assist in identifying those with unhealthy alcohol use.
Imaging Transient elastography (FibroScan; Echosens, Waltham, MA, USA) is a noninvasive tool for the assessment of fibrosis in chronic liver disease. The cirrhosis detection value is between 12.5 and 14.6 kPa.2 Ultrasound, magnetic resonance imaging, and computed tomographic imaging are used to assess for the presence of steatosis, advanced fibrosis, cirrhosis, and manifestations of portal hypertension, as well as to look for and assess for ascites and portal vein thrombosis. Ultrasound imaging is widely used because of its low cost, although its sensitivity and specificity in the setting of mild steatosis are low.2 Liver Biopsy Liver biopsy is not advised when high suspicion is unequivocal based on clinical findings, laboratory patterns, history taking, and imaging data. On the other hand, it may assist the clinician in ruling out other nonealcohol-related liver causes or when the data at hand are not conclusive. Liver biopsies may be done percutaneously; however, in cases with concerns for coagulopathy or when measurement of hepatic portal pressures are indicated, the transjugular route is preferred.2 Typical liver biopsy findings in ALD are steatosis, hepatocellular damage (ballooning and/or Mallory-Denk bodies), inflammatory infiltrates, fluctuating degree of fibrosis, and lobular distortion. These findings may cause progression to cirrhosis.6 Subjective/Clinical Presentation Subjective and/or clinical presentation may range from vague early symptoms, such as fatigue, nausea, vomiting, anorexia, and physical findings of chronic use of alcohol, to advanced liver disease symptomology. Clinical indicators may be present in ultrasound imaging as hepatic steatosis and laboratories showing elevated blood alcohol, elevated urinary ethyl glucuronide, aspartate aminotransferase > alanine aminotransferase, serum bilirubin < 3, or elevated gamma-glutamyl-transferase (transpeptidase).2 Predictors of Mortality The following models that assist in predicting outcomes in individuals with alcoholic hepatitis may also assist in therapy determination: 1. The Maddrey discriminant function (DF): a DF value 32 indicates a high short-term mortality risk (35% at 1 month) as well as selecting patients for corticosteroid (CS) therapy.6
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2. The Model for End-Stage Liver Disease Sodium: this is a statistical model that incorporates serum bilirubin, serum creatinine, serum sodium, and the international normalized ratio and provides a 3-month mortality risk percentage in patients with cirrhosis.8 3. The Lille model: this assesses the response to CS therapy to guide patients’ prognosis. It measures changes in serum bilirubin after 1 week of CS. In nonresponders, discontinuation of CS is recommended because risks and complications can outweigh benefits.8 The Lille model provides a cutoff at 0.45; scores < 0.45 are consistent with a 6-month survival rate of 85%. On the other hand, scores > 0.45 indicate a 6-month survival of 25% and should warrant consideration of alternative therapies, as well as referral for LT consideration.9
Alcohol Withdrawal Management Alcohol withdrawal syndrome affects those dependent on alcohol who suddenly stop or greatly reduce their intake. Less severe symptoms may be exhibited within 6 to 24 hours after the last alcohol intake, but severity can advance with patients exhibiting delirium tremens, seizures, coma, cardiac arrest, and even death. Intensive care unit monitoring should be pursued in those patients with moderate to severe alcohol withdrawal. Benzodiazepines are the drug of choice; long-acting benzodiazepines safeguard against seizures and delirium, whereas short- and intermediate-acting benzodiazepines are the choice for patients with compromised liver function.4 Box 2 provides a general overview of management of alcoholic cirrhosis.
Treatment Pharmacotherapy Supportive Primary care providers can make a difference in slowing or stopping alcohol-related complications with early identification and interventions in those patients with worrisome alcohol use. Unfortunately, primary care providers identify only about 10% of patients who abuse alcohol; furthermore, teenagers are often underdiagnosed. Referral to a qualified counselor could have a great impact, such as abstinence rates of 17% to 33%, with an additional 7% to 12% of patients reducing their alcohol intake.7 Abstinence The main goal for patients with ALD is immediate and ultimately long-term alcohol abstinence using treatments that combine psychosocial interventions, pharmacologic therapy, and medical management. This requires a multidisciplinary approach involving practitioners, addiction specialists, and psychosocial providers. Furthermore, to more effectively promote abstinence, practitioners must identify and treat associated psychological disorders such as depression, anxiety, posttraumatic stress disorder, psychosis, and affective disorders. Also, further investigation should be conducted into past sexual abuse trauma, violent tendencies, driving under the influence, and social separation. Sleeping disorders and uncontrolled chronic pain may be precipitators for alcohol abuse. These patients also have a higher propensity to drug addictions and tobacco dependency.4 Nutrition Malnutrition in the setting of AH is common and is an impediment to recuperation. Patients consuming < 21.5 kcal/kg/ d were at risk for higher mortality. Proper nutrition and assisting patients in meeting their nutritional goals are paramount. Despite previous thinking, average- to high-content protein diets do not put patients at higher risk for developing encephalopathy.10 The preferred feeding mode is the enteral route because it is safe even in the setting of nonactive bleeding esophageal varices or in patients who recently have had endoscopic variceal banding. There is also a lower propensity for infections, and treatment costs are lower overall. Nutritional daily intakes of calories of 35 kcal/kg and protein of 1.2 to 1.5 g/kg are recommended. Zinc, thiamine, and B complex along with other trace elements will likely need replacement as well. Intravenous volume replacement is best achieved with albumin.4
Current research has shown that only baclofen has shown efficacy and safety in achieving higher rates of abstinence.4 Disulfiram and naltrexone are potentially hepatotoxic and therefore are contraindicated in ALD patients. Nalmefene is a recently approved medication by the Food and Drug Administration.6 Currently, there is no specific therapy in the treatment of advanced cases of liver disease and AH, with little progress made in this field. The first-line therapeutic option is prednisolone in those with severe AH, as recent studies have questioned using pentoxifylline.2 Prednisolone is preferred because prednisone requires hepatic conversion to prednisolone, its active form.11 The most recent guidelines direct clinicians to start prednisolone 40 mg daily for 1 month, with or without a taper, because it has shown increased survival rates in patients with a high DF. However, in nonresponders, after 1 week of treatment (Lille model scores > 0.45), discontinuation of prednisolone is recommended because there is an increased risk of developing pulmonary infections, especially invasive aspergillosis. Early referral for LT consideration should be made in selected patients, as well as frank discussion about goals of care in those patients with multiorgan failure.4
Box 2. General Management of Alcoholic Cirrhosis4 Initial screening for esophageal varices with upper gastrointestinal endoscopy Surveillance for hepatocellular carcinoma should be performed every 6 months with an ultrasound because there is a lifelong risk of about 3% to 10%. Immunizations: hepatitis A and B, pneumococcal pneumonia, and influenza For those patients decompensated: Ascites: diagnostic paracentesis to rule out spontaneous bacterial peritonitis; if diagnosed, then immediate initiation of antibiotics plus albumin 1.5 g/kg on day 1 and 1 g/ kg on day 3. Hepatic encephalopathy: use lactulose and rifaximin. Treat infections accordingly. Rule out other potential causes of altered mental status such as drug overdose, subdural hematoma, stroke, meningitis, and central nervous system fungal infections. Acute variceal bleeding: requires treatment with vasoactive agents such as octreotide, antibiotics, and endoscopic therapy
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CS therapy acts by modifying the balance of cytokines, lowering proinflammatory cytokines, and increasing anti-inflammatory cytokines.10 Contraindications to using CS in severe hepatitis (DF > 32) are acute infection, acute kidney injury (usually hepatorenal syndrome), gastrointestinal bleeding, acute pancreatitis, and other clear contraindications to steroids.12 Intensive Care Support Extrahepatic organ failure will likely require transfer to an intensive care unit setting. Ongoing surveillance for sepsis with initiation of broad-spectrum antibiotics as soon as there is a strong suspicion should be performed. A low threshold for diagnosis of an infection is essential because sepsis is difficult to diagnose; up to 40% to 50% of patients’ cultures can be negative (Box 3).4 Liver Transplant Liver transplant (LT) is a lifesaving treatment option for patients with cirrhosis and end-stage liver disease. Alcoholic-induced cirrhosis is now the third most common indication for LT (HCV and nonalcoholic fatty liver disease being at the top). In the US, alcohol-induced cirrhosis accounts for approximately 15% of all LTs.4 Morbidity and mortality after undergoing LT are practically the same as for those transplanted for other etiologies. However, cardiovascular-related deaths, chronic kidney disease, and new development of cancers in the transplanted ALD population are higher, especially taking into consideration cigarette smoking, which is commonly seen in patients transplanted for ALD.6 Transplanting patients for ALD is now becoming a more accepted practice because there exists an exceptionally rare incidence of alcohol recidivism leading to harmful drinking after a transplant, which is likely attributed to the strict selection criteria guidelines. In patients transplanted for ALD, according to the European Liver Transplant Registry, survival rates of 84%, 78%, 73%, and 58% after 1, 3, 5, and 10 years, respectively, are
Box 3. Intensive Care in the Presence of Extrahepatic Organ Failure4 Piperacillin/tazobactam is the drug of choice. Consider vancomycin and meropenem in patients with hypersensitivity to penicillin. Coverage for atypical organisms and fungal infections in high-risk patients Ulcer prophylaxis with proton-pump inhibitors Glucose control to aim for levels < 200 Blood transfusions to maintain a hemoglobin around 7 to 8 g/dL In renal failure and acute kidney injury (AKI), the goal is to identify, reverse precipitating factors, and ultimately improve renal function. Renal replacement therapy (RRT) is recommended in the setting of AKI with sepsis-related acute tubular necrosis or an unclear cause for AKI. For hepatorenal syndrome, a therapeutic trial of RRT can be considered in potential liver transplant candidates. Pulmonary support should use low tidal volume to try to prevent injury to the lungs. Vasopressors if needed to maintain a mean blood pressure of > 65 mm Hg
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superior to those with viral hepatitis and cryptogenic cirrhosis. Posttransplant follow-up, especially in the first few months, is essential to manage and hopefully prevent or decrease transplant and immunosuppression-related complications, such as worsening or de novo diabetes mellitus, hypertension, dyslipidemia, cancers, chronic kidney disease, etc.6 Disparities currently exist within the referral process of patients with alcoholic cirrhosis because most transplant centers have a strict 6-month period of required complete abstinence from alcohol. This excludes the majority of patients with severe alcoholic hepatitis and nonresponders to CS therapy; these patients tend to die before meeting the required abstinence period time line. Also, providers may exhibit bias against referral for transplant evaluation in patients with alcoholic cirrhosis. Prospective studies have been performed to advocate for earlier transplant consideration in carefully selected patients who can show good social support and a favorable prognosis from a psychological standpoint because it can improve survival drastically.2 Research and Future Treatments in the Works Challenges exist to the emergence of new therapies that demonstrate a sustainable response as well as mitigate the potential of deadly infections in this population.2 There is a trial currently analyzing the impact of gut microbiota on liver fibrosis using placebo versus 550 mg rifaximin twice daily for 18 months. In the discussion, the authors postulate that if gut microbiota is an important inducer of alcoholic liver disease, then modulation of gut flora may be an innovative way to improve outcomes in liver disease and unlock new options for therapy as well as transform our present understanding of chronic liver diseases.12 The National Institute on Alcohol Abuse and Alcoholism is currently exploring new therapies for the management of AH. Ongoing clinical trials are targeting different mechanisms in AH pathophysiology such as altered gut-barrier function that can cause bacterial and endotoxin translocation, hepatic innate immune system activation, hepatocellular apoptosis, necrosis, and injury. One study is looking into oral zinc, 220 mg daily, to maintain function of the gut barrier, lessen liver inflammation, and improve fibrosis biomarkers and liver function, as well as clinical indicators in alcoholic cirrhosis.13 Practice Implications for the APP There exists a great need to explore newer and safer therapies to treat AH and other modalities to lessen alcohol abuse. High longterm mortality is likely a result of patients relapsing and going back to active drinking.10 Greater interest from researchers in this field along with more funds from the National Institute of Alcoholism and Alcohol Abuse and other institutions could help tackle this unmet need.4 Referral to LT centers that offer early access should be made to those patients who have not responded appropriately to medical therapy and can show a stable psychosocial profile.13 APPs can become actively involved in leading efforts to best serve this population by further exploring areas such as epidemiology, prevention modalities, and newer, safer, and more efficacious pharmacologic therapies. Care of this population requires a multidisciplinary approach. It is crucial that APPs are well-informed about this disease process as they are likely to be involved in the care of these patients in both primary and acute care practice settings.
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References 1. World Health Organization. Management of substance abuse. Alcohol. http:// www.who.int/substance_abuse/facts/alcohol/en/. Accessed October 10, 2018. 2. Mathurin P, Bataller R. Trends in the management and burden of alcoholic liver disease. J Hepatol. 2015;62(suppl):S38-S46. https://doi.org/10.1016/ j.jhep.2015.03.006. 3. Centers for Disease Control and Prevention. Alcohol and public health. Public health surveillance. Data and maps. https://www.cdc.gov/alcohol/data-stats. htm. Accessed October 10, 2018. 4. Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol. 2018;113(2):175-194. https:// doi.org/10.1038/ajg.2017.469. 5. Dugum M, Mccullough A. Diagnosis and management of alcoholic liver disease. J Clin Transl Hepatol. 2015;3(2):109-116. https://doi.org/10.14218/ JCTH.2015.00008. 6. Stickel F, Datz C, Hampe J, Bataller R. Pathophysiology and management of alcoholic liver disease: update 2016. Gut Liver. 2017;11(2):173-188. https:// doi.org/10.5009/gnl16477. 7. Kling CE, Perkins JD, Carithers RL, Donovan DM, Sibulesky L. Recent trends in liver transplantation for alcoholic liver disease in the United States. World J Hepatol. 2017;9(36):1315-1321. https://doi.org/10.4254/wjh.v9.i36.1315. 8. MDApp. MELD NA score. https://www.mdapp.co/meld-na-score-calculator174/. Accessed November 14, 2018.
9. MDApp. Alcoholic hepatitis Lille score. https://www.mdapp.co/alcoholichepatitis-lille-score-calculator-178/. Accessed September 23, 2018. 10. Mitchell MC, Friedman LS, Mcclain CJ. Medical management of severe alcoholic hepatitis: expert review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol. 2017;15(1):5-12. https://doi.org/ 10.1016/j.cgh.2016.08.047. 11. Saberi B, Dadabhai AS, Jang YY, Gurakar A, Mezey E. Current management of alcoholic hepatitis and future therapies. J Clin Transl Hepatol. 2016;4(2): 113-122. https://doi.org/10.14218/JCTH.2016.00006. 12. Madsen BS, Trebicka J, Thiele M, et al. Antifibrotic and molecular aspects of rifaximin in alcoholic liver disease: study protocol for a randomized controlled trial. Trials. 2018;19(1):143. https://doi.org/10.1186/s13063018-2523-9. 13. Im GY, Lucey MR. Practical concerns and controversies in the management of alcoholic hepatitis. Gastroenterol Hepatol (N Y). 2016;12(8): 478-489.
Hender Rojas, MSN, ACNP-BC, is a nurse practitioner with the Department of Surgery, Transplant Division at the University of Kentucky HealthCare in Lexington. He is available at [email protected]. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.
Contents lists available at ScienceDirect
The Journal for Nurse Practitioners journal homepage: www.npjournal.org
Alcoholic Liver Disease: Implications for the Advanced Practice Provider Hender Rojas, MSN, ACNP-BC a b s t r a c t Keywords: alcoholic hepatitis alcoholic liver disease alcohol use disorder alcohol withdrawal syndrome liver transplantation
Alcoholic liver disease is a largely preventable condition that contributes to mortality in the United States and worldwide. This article discusses the pathogenesis, risk factors, diagnosis, screening tools, clinical presentation, and predictors of mortality. Medical management using the most recent clinical guidelines from the 2018 American College of Gastroenterology and the American Gastroenterological Association Institute are reviewed. Supportive care, abstinence promotion, cognitive behavioral therapy, nutritional needs, pharmacotherapy, alcohol withdrawal management, intensive care, and liver transplantation are discussed, as well as future research directions. Finally, practice implications to better address this population’s needs using a multidisciplinary approach are addressed. © 2019 Elsevier Inc. All rights reserved.
Alcohol abuse is 1 of the main causes of preventable liverrelated disease that contributes to mortality in the United States and worldwide. Alcohol is a psychoactive substance that can cause dependence. The unhealthy use of alcohol burdens communities with disease and social and economic stress. The amount and pattern of alcohol use have a direct relation to its harmful properties.1 The causes of liver disease vary across the world. For example, in Asia and Africa, viral hepatitis is the driving factor, whereas in North America and Europe, it is primarily attributed to alcohol abuse.2 According to the World Health Organization, alcohol abuse causes over 200 disease conditions, including dependence on alcohol, cirrhosis, and cancers, as well as injuries. Furthermore, in 2012, about 3.3 million deaths, or 5.9% of all global deaths, were related to the consumption of alcohol.1 Estimations done by the Centers for Disease Control and Prevention in 2010 put the price of excessive alcohol consumption in the US at $249 billion, mainly related to losses in workplace productivity (72% of the total cost), health care costs, and a combination of criminal justice, motor vehicle crash, and property damage expenses.3 The National Institute of Alcoholism and Alcohol Abuse defines alcohol use disorder (AUD) as the consumption of > 3 drinks per day in males and > 2 drinks per day in females for > 5 years and binge drinking as the consumption of > 5 drinks in males and > 4 drinks in females within a 2-hour period. By these definitions, about 1 in 12 adults have AUD. In the US, 1 drink is quantified as a beverage holding about 14 g alcohol (12 oz beer, 5 oz wine, or 1.5 oz hard liquor).4 https://doi.org/10.1016/j.nurpra.2019.04.002 1555-4155/© 2019 Elsevier Inc. All rights reserved.
The care of these patients requires a multidisciplinary approach. It is crucial that advanced practice providers (APPs) are wellinformed about this disease process as they are likely to be involved in the care of these patients in both primary and acute care practice settings. This article discusses pathogenesis, risk factors, diagnosis, screening tools for alcohol abuse, clinical presentation, and predictors of mortality that are associated with alcoholic liver disease (ALD). Medical management using the most recent clinical guidelines from the American College of Gastroenterology for the management of ALD (2018) and the evidence-based clinical practice updates from the expert review from the Clinical Practice Updates Committee of the American Gastroenterological Association Institute (2017) for severe acute alcoholic hepatitis are discussed. Supportive care, abstinence promotion, cognitive behavioral therapy, nutritional needs, pharmacotherapy, alcohol withdrawal management, intensive care, and liver transplantation (LT) are reviewed. Research and future directions for treatment and management are considered. Finally, practice implications for the APP to better address this population’s needs using a multidisciplinary approach are discussed. Pathogenesis: Natural Progression From Steatosis to Cirrhosis ALD encompasses a spectrum of liver pathology. Initially, fatty liver changes are generally asymptomatic but evident in the great majority of heavy alcohol drinkers. These hepatic changes can be generally reversed once alcohol use is discontinued. Alcohol use can be a contributing factor in accelerating hepatic fibrosis in patients who may also have other types of liver disease, such as
H. Rojas / The Journal for Nurse Practitioners 15 (2019) 506e510
hepatitis C virus (HCV).4 Up to 20% to 40% of alcoholics develop fibrosis, and 10% to 20% eventually progress to cirrhosis. Furthermore, 1% to 2% of patients with cirrhosis are diagnosed with hepatocellular carcinoma annually.5 Hepatic-related complications as a result of cirrhosis include portal hypertension, spontaneous bacterial peritonitis, ascites, hepatic encephalopathy, variceal bleeding, hydrothorax, hepatopulmonary syndrome, and hepatorenal syndrome. Alcoholic hepatitis (AH) can be found in patients with advanced fibrosis or established cirrhosis with concurrent heavy use of alcohol. Patients with AH will present with hepatic complications, jaundice, and a sharp increase in serum bilirubin. AH patients’ short-term mortality rate can be very high, up to 30% to 50% at 3 months.2
Risk Factors: Disease Modifiers and Cofactors According to Singal et al, approximately 10% to 20% of patients with ongoing alcohol abuse progress to advanced liver disease and cirrhosis. Behavioral, environmental, and genetic factors may possibly play a role as contributing factors and disease modifiers.4 Sex differences account for variance when comparing the amount of alcohol use and developing ALD. For example, females, who are more likely to have a high body fat content as well as lower gastric alcohol dehydrogenase activity, are more at risk for ALD with lower amounts of daily alcohol use.4 Environmental risk factors are significant in disease progression to cirrhosis; for example, obesity coupled with heavy alcohol use doubles the likelihood of individuals progressing to cirrhosis.2 Cigarette smoking, elevated iron levels, and having concurrent hepatitis B or HCV infection increases the risk of liver injury, cirrhosis, hepatic decompensation, and hepatocellular carcinoma.4 On the other hand, the consumption of coffee has been shown to have protective properties against alcoholinduced liver injury when 4 or more cups are consumed per day; coffee drinkers have a lower risk of advancing to cirrhosis versus those who are not coffee drinkers.6 Genetic factors such as modifiers of neurotransmission (gamma-aminobutyric) and alcohol metabolism (alcoholic dehydrogenase and acetaldehyde dehydrogenase enzymes) may decrease the threshold to resist alcohol consumption or may enhance susceptibility in those who already have AUD to further progress to ALD. Several large studies have shown that the principal genetic patatinlike phospholipase domain containing protein 3 (PNPLA3), could be the primary factor that decisively affects the risk and severity of ALD.4
Diagnosis ALD in the early clinical stages has minimal or no symptoms in most patients, as well as in those who have compensated cirrhosis. Therefore, diagnosis in this setting relies on clinical suspicion, documentation of excessive alcohol consumption, laboratory findings, imaging, and, if needed, a liver biopsy. The clinician needs to be cognizant that self-reports of alcohol use frequently downplay the actual consumption pattern and quantity; if appropriate, relatives and friends may provide useful information. Suspicion for AUD diagnosis is confirmed when excessive alcohol consumption (> 40-50 g/d) is documented, along with abnormal clinical and/or biological findings pointing toward liver injury.6 Box 1 discusses screening tools for alcohol abuse.
507
Box 1. Screening Tools for Alcohol Use7 The CAGE questionnaire is a 4-question test with binary answers; 2 “yes” responses are considered a positive test eliciting additional testing. The Alcohol Use Disorders Inventory Test consists of 10 questions with 5 possible answers and a focus on the identification of heavy drinkers. A single screening question “How many times in the past year have you had 5 drinks (males) or 4 drinks (females) or more in a day?” may assist in identifying those with unhealthy alcohol use.
Imaging Transient elastography (FibroScan; Echosens, Waltham, MA, USA) is a noninvasive tool for the assessment of fibrosis in chronic liver disease. The cirrhosis detection value is between 12.5 and 14.6 kPa.2 Ultrasound, magnetic resonance imaging, and computed tomographic imaging are used to assess for the presence of steatosis, advanced fibrosis, cirrhosis, and manifestations of portal hypertension, as well as to look for and assess for ascites and portal vein thrombosis. Ultrasound imaging is widely used because of its low cost, although its sensitivity and specificity in the setting of mild steatosis are low.2 Liver Biopsy Liver biopsy is not advised when high suspicion is unequivocal based on clinical findings, laboratory patterns, history taking, and imaging data. On the other hand, it may assist the clinician in ruling out other nonealcohol-related liver causes or when the data at hand are not conclusive. Liver biopsies may be done percutaneously; however, in cases with concerns for coagulopathy or when measurement of hepatic portal pressures are indicated, the transjugular route is preferred.2 Typical liver biopsy findings in ALD are steatosis, hepatocellular damage (ballooning and/or Mallory-Denk bodies), inflammatory infiltrates, fluctuating degree of fibrosis, and lobular distortion. These findings may cause progression to cirrhosis.6 Subjective/Clinical Presentation Subjective and/or clinical presentation may range from vague early symptoms, such as fatigue, nausea, vomiting, anorexia, and physical findings of chronic use of alcohol, to advanced liver disease symptomology. Clinical indicators may be present in ultrasound imaging as hepatic steatosis and laboratories showing elevated blood alcohol, elevated urinary ethyl glucuronide, aspartate aminotransferase > alanine aminotransferase, serum bilirubin < 3, or elevated gamma-glutamyl-transferase (transpeptidase).2 Predictors of Mortality The following models that assist in predicting outcomes in individuals with alcoholic hepatitis may also assist in therapy determination: 1. The Maddrey discriminant function (DF): a DF value 32 indicates a high short-term mortality risk (35% at 1 month) as well as selecting patients for corticosteroid (CS) therapy.6
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H. Rojas / The Journal for Nurse Practitioners 15 (2019) 506e510
2. The Model for End-Stage Liver Disease Sodium: this is a statistical model that incorporates serum bilirubin, serum creatinine, serum sodium, and the international normalized ratio and provides a 3-month mortality risk percentage in patients with cirrhosis.8 3. The Lille model: this assesses the response to CS therapy to guide patients’ prognosis. It measures changes in serum bilirubin after 1 week of CS. In nonresponders, discontinuation of CS is recommended because risks and complications can outweigh benefits.8 The Lille model provides a cutoff at 0.45; scores < 0.45 are consistent with a 6-month survival rate of 85%. On the other hand, scores > 0.45 indicate a 6-month survival of 25% and should warrant consideration of alternative therapies, as well as referral for LT consideration.9
Alcohol Withdrawal Management Alcohol withdrawal syndrome affects those dependent on alcohol who suddenly stop or greatly reduce their intake. Less severe symptoms may be exhibited within 6 to 24 hours after the last alcohol intake, but severity can advance with patients exhibiting delirium tremens, seizures, coma, cardiac arrest, and even death. Intensive care unit monitoring should be pursued in those patients with moderate to severe alcohol withdrawal. Benzodiazepines are the drug of choice; long-acting benzodiazepines safeguard against seizures and delirium, whereas short- and intermediate-acting benzodiazepines are the choice for patients with compromised liver function.4 Box 2 provides a general overview of management of alcoholic cirrhosis.
Treatment Pharmacotherapy Supportive Primary care providers can make a difference in slowing or stopping alcohol-related complications with early identification and interventions in those patients with worrisome alcohol use. Unfortunately, primary care providers identify only about 10% of patients who abuse alcohol; furthermore, teenagers are often underdiagnosed. Referral to a qualified counselor could have a great impact, such as abstinence rates of 17% to 33%, with an additional 7% to 12% of patients reducing their alcohol intake.7 Abstinence The main goal for patients with ALD is immediate and ultimately long-term alcohol abstinence using treatments that combine psychosocial interventions, pharmacologic therapy, and medical management. This requires a multidisciplinary approach involving practitioners, addiction specialists, and psychosocial providers. Furthermore, to more effectively promote abstinence, practitioners must identify and treat associated psychological disorders such as depression, anxiety, posttraumatic stress disorder, psychosis, and affective disorders. Also, further investigation should be conducted into past sexual abuse trauma, violent tendencies, driving under the influence, and social separation. Sleeping disorders and uncontrolled chronic pain may be precipitators for alcohol abuse. These patients also have a higher propensity to drug addictions and tobacco dependency.4 Nutrition Malnutrition in the setting of AH is common and is an impediment to recuperation. Patients consuming < 21.5 kcal/kg/ d were at risk for higher mortality. Proper nutrition and assisting patients in meeting their nutritional goals are paramount. Despite previous thinking, average- to high-content protein diets do not put patients at higher risk for developing encephalopathy.10 The preferred feeding mode is the enteral route because it is safe even in the setting of nonactive bleeding esophageal varices or in patients who recently have had endoscopic variceal banding. There is also a lower propensity for infections, and treatment costs are lower overall. Nutritional daily intakes of calories of 35 kcal/kg and protein of 1.2 to 1.5 g/kg are recommended. Zinc, thiamine, and B complex along with other trace elements will likely need replacement as well. Intravenous volume replacement is best achieved with albumin.4
Current research has shown that only baclofen has shown efficacy and safety in achieving higher rates of abstinence.4 Disulfiram and naltrexone are potentially hepatotoxic and therefore are contraindicated in ALD patients. Nalmefene is a recently approved medication by the Food and Drug Administration.6 Currently, there is no specific therapy in the treatment of advanced cases of liver disease and AH, with little progress made in this field. The first-line therapeutic option is prednisolone in those with severe AH, as recent studies have questioned using pentoxifylline.2 Prednisolone is preferred because prednisone requires hepatic conversion to prednisolone, its active form.11 The most recent guidelines direct clinicians to start prednisolone 40 mg daily for 1 month, with or without a taper, because it has shown increased survival rates in patients with a high DF. However, in nonresponders, after 1 week of treatment (Lille model scores > 0.45), discontinuation of prednisolone is recommended because there is an increased risk of developing pulmonary infections, especially invasive aspergillosis. Early referral for LT consideration should be made in selected patients, as well as frank discussion about goals of care in those patients with multiorgan failure.4
Box 2. General Management of Alcoholic Cirrhosis4 Initial screening for esophageal varices with upper gastrointestinal endoscopy Surveillance for hepatocellular carcinoma should be performed every 6 months with an ultrasound because there is a lifelong risk of about 3% to 10%. Immunizations: hepatitis A and B, pneumococcal pneumonia, and influenza For those patients decompensated: Ascites: diagnostic paracentesis to rule out spontaneous bacterial peritonitis; if diagnosed, then immediate initiation of antibiotics plus albumin 1.5 g/kg on day 1 and 1 g/ kg on day 3. Hepatic encephalopathy: use lactulose and rifaximin. Treat infections accordingly. Rule out other potential causes of altered mental status such as drug overdose, subdural hematoma, stroke, meningitis, and central nervous system fungal infections. Acute variceal bleeding: requires treatment with vasoactive agents such as octreotide, antibiotics, and endoscopic therapy
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CS therapy acts by modifying the balance of cytokines, lowering proinflammatory cytokines, and increasing anti-inflammatory cytokines.10 Contraindications to using CS in severe hepatitis (DF > 32) are acute infection, acute kidney injury (usually hepatorenal syndrome), gastrointestinal bleeding, acute pancreatitis, and other clear contraindications to steroids.12 Intensive Care Support Extrahepatic organ failure will likely require transfer to an intensive care unit setting. Ongoing surveillance for sepsis with initiation of broad-spectrum antibiotics as soon as there is a strong suspicion should be performed. A low threshold for diagnosis of an infection is essential because sepsis is difficult to diagnose; up to 40% to 50% of patients’ cultures can be negative (Box 3).4 Liver Transplant Liver transplant (LT) is a lifesaving treatment option for patients with cirrhosis and end-stage liver disease. Alcoholic-induced cirrhosis is now the third most common indication for LT (HCV and nonalcoholic fatty liver disease being at the top). In the US, alcohol-induced cirrhosis accounts for approximately 15% of all LTs.4 Morbidity and mortality after undergoing LT are practically the same as for those transplanted for other etiologies. However, cardiovascular-related deaths, chronic kidney disease, and new development of cancers in the transplanted ALD population are higher, especially taking into consideration cigarette smoking, which is commonly seen in patients transplanted for ALD.6 Transplanting patients for ALD is now becoming a more accepted practice because there exists an exceptionally rare incidence of alcohol recidivism leading to harmful drinking after a transplant, which is likely attributed to the strict selection criteria guidelines. In patients transplanted for ALD, according to the European Liver Transplant Registry, survival rates of 84%, 78%, 73%, and 58% after 1, 3, 5, and 10 years, respectively, are
Box 3. Intensive Care in the Presence of Extrahepatic Organ Failure4 Piperacillin/tazobactam is the drug of choice. Consider vancomycin and meropenem in patients with hypersensitivity to penicillin. Coverage for atypical organisms and fungal infections in high-risk patients Ulcer prophylaxis with proton-pump inhibitors Glucose control to aim for levels < 200 Blood transfusions to maintain a hemoglobin around 7 to 8 g/dL In renal failure and acute kidney injury (AKI), the goal is to identify, reverse precipitating factors, and ultimately improve renal function. Renal replacement therapy (RRT) is recommended in the setting of AKI with sepsis-related acute tubular necrosis or an unclear cause for AKI. For hepatorenal syndrome, a therapeutic trial of RRT can be considered in potential liver transplant candidates. Pulmonary support should use low tidal volume to try to prevent injury to the lungs. Vasopressors if needed to maintain a mean blood pressure of > 65 mm Hg
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superior to those with viral hepatitis and cryptogenic cirrhosis. Posttransplant follow-up, especially in the first few months, is essential to manage and hopefully prevent or decrease transplant and immunosuppression-related complications, such as worsening or de novo diabetes mellitus, hypertension, dyslipidemia, cancers, chronic kidney disease, etc.6 Disparities currently exist within the referral process of patients with alcoholic cirrhosis because most transplant centers have a strict 6-month period of required complete abstinence from alcohol. This excludes the majority of patients with severe alcoholic hepatitis and nonresponders to CS therapy; these patients tend to die before meeting the required abstinence period time line. Also, providers may exhibit bias against referral for transplant evaluation in patients with alcoholic cirrhosis. Prospective studies have been performed to advocate for earlier transplant consideration in carefully selected patients who can show good social support and a favorable prognosis from a psychological standpoint because it can improve survival drastically.2 Research and Future Treatments in the Works Challenges exist to the emergence of new therapies that demonstrate a sustainable response as well as mitigate the potential of deadly infections in this population.2 There is a trial currently analyzing the impact of gut microbiota on liver fibrosis using placebo versus 550 mg rifaximin twice daily for 18 months. In the discussion, the authors postulate that if gut microbiota is an important inducer of alcoholic liver disease, then modulation of gut flora may be an innovative way to improve outcomes in liver disease and unlock new options for therapy as well as transform our present understanding of chronic liver diseases.12 The National Institute on Alcohol Abuse and Alcoholism is currently exploring new therapies for the management of AH. Ongoing clinical trials are targeting different mechanisms in AH pathophysiology such as altered gut-barrier function that can cause bacterial and endotoxin translocation, hepatic innate immune system activation, hepatocellular apoptosis, necrosis, and injury. One study is looking into oral zinc, 220 mg daily, to maintain function of the gut barrier, lessen liver inflammation, and improve fibrosis biomarkers and liver function, as well as clinical indicators in alcoholic cirrhosis.13 Practice Implications for the APP There exists a great need to explore newer and safer therapies to treat AH and other modalities to lessen alcohol abuse. High longterm mortality is likely a result of patients relapsing and going back to active drinking.10 Greater interest from researchers in this field along with more funds from the National Institute of Alcoholism and Alcohol Abuse and other institutions could help tackle this unmet need.4 Referral to LT centers that offer early access should be made to those patients who have not responded appropriately to medical therapy and can show a stable psychosocial profile.13 APPs can become actively involved in leading efforts to best serve this population by further exploring areas such as epidemiology, prevention modalities, and newer, safer, and more efficacious pharmacologic therapies. Care of this population requires a multidisciplinary approach. It is crucial that APPs are well-informed about this disease process as they are likely to be involved in the care of these patients in both primary and acute care practice settings.
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References 1. World Health Organization. Management of substance abuse. Alcohol. http:// www.who.int/substance_abuse/facts/alcohol/en/. Accessed October 10, 2018. 2. Mathurin P, Bataller R. Trends in the management and burden of alcoholic liver disease. J Hepatol. 2015;62(suppl):S38-S46. https://doi.org/10.1016/ j.jhep.2015.03.006. 3. Centers for Disease Control and Prevention. Alcohol and public health. Public health surveillance. Data and maps. https://www.cdc.gov/alcohol/data-stats. htm. Accessed October 10, 2018. 4. Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol. 2018;113(2):175-194. https:// doi.org/10.1038/ajg.2017.469. 5. Dugum M, Mccullough A. Diagnosis and management of alcoholic liver disease. J Clin Transl Hepatol. 2015;3(2):109-116. https://doi.org/10.14218/ JCTH.2015.00008. 6. Stickel F, Datz C, Hampe J, Bataller R. Pathophysiology and management of alcoholic liver disease: update 2016. Gut Liver. 2017;11(2):173-188. https:// doi.org/10.5009/gnl16477. 7. Kling CE, Perkins JD, Carithers RL, Donovan DM, Sibulesky L. Recent trends in liver transplantation for alcoholic liver disease in the United States. World J Hepatol. 2017;9(36):1315-1321. https://doi.org/10.4254/wjh.v9.i36.1315. 8. MDApp. MELD NA score. https://www.mdapp.co/meld-na-score-calculator174/. Accessed November 14, 2018.
9. MDApp. Alcoholic hepatitis Lille score. https://www.mdapp.co/alcoholichepatitis-lille-score-calculator-178/. Accessed September 23, 2018. 10. Mitchell MC, Friedman LS, Mcclain CJ. Medical management of severe alcoholic hepatitis: expert review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol. 2017;15(1):5-12. https://doi.org/ 10.1016/j.cgh.2016.08.047. 11. Saberi B, Dadabhai AS, Jang YY, Gurakar A, Mezey E. Current management of alcoholic hepatitis and future therapies. J Clin Transl Hepatol. 2016;4(2): 113-122. https://doi.org/10.14218/JCTH.2016.00006. 12. Madsen BS, Trebicka J, Thiele M, et al. Antifibrotic and molecular aspects of rifaximin in alcoholic liver disease: study protocol for a randomized controlled trial. Trials. 2018;19(1):143. https://doi.org/10.1186/s13063018-2523-9. 13. Im GY, Lucey MR. Practical concerns and controversies in the management of alcoholic hepatitis. Gastroenterol Hepatol (N Y). 2016;12(8): 478-489.
Hender Rojas, MSN, ACNP-BC, is a nurse practitioner with the Department of Surgery, Transplant Division at the University of Kentucky HealthCare in Lexington. He is available at [email protected]. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.