Alcoholic Liver Disease

Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Diagnosis is based on a history of alcohol abuse and confirmed by laboratory derangement with an AST/ALT ratio > 2. Alcoholic liver disease carries a high mortality rate if patients present with severe hepatitis. Management aims at alcohol abstinence for reversal (at certain stages) and addressing contributing factors (such as viral infections or drugs) to minimize damage to the hepatocytes. Approximately 10% of patients regress with alcohol abstinence during the hepatitis stage. Cirrhosis is frequently irreversible.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Alcoholic liver disease encompasses alcoholic steatosis (fatty liver, reversible), steatohepatitis (can be reversible), and cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis (irreversible). All are secondary to alcohol abuse.

Three stages of alcoholic liver disease

The 3 stages of alcoholic liver disease:
These 3 stages of alcoholic liver disease may overlap and do not necessarily occur in sequence: alcoholic fatty liver (reversible), alcoholic hepatitis (reversible if alcohol stopped), and alcohol-related cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis (irreversible). They are also risk factors for developing hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases ( HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases).

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Epidemiology

  • Prevalence of alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder in the United States is 18%.
  • The disease is the 2nd most common cause of cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis in the United States.
  • Prevalence of alcoholic fatty liver disease is 4% in the United States.
  • Alcoholic hepatitis develops in about 35% of alcoholics.
  • About 15%–20% of heavy drinkers will develop cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis.
  • Age of presentation is usually before 60 years old.
  • High mortality rate in severe alcoholic liver disease: if left untreated → 45% in 1 month

Etiology

  • Main causative factor is heavy alcohol consumption:
    • Men: > 40 g/day
    • Women: > 20 g/day
  • Risk factors for the development of alcoholic liver disease include:
    • Women with increased susceptibility
    • Hepatitis C virus Hepatitis C Virus Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus ( HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus) infection
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity and non-alcoholic fatty liver disease
    • High-fat diet
    • Smoking
    • Diabetes

Pathophysiology

Ethanol metabolism Ethanol metabolism Ethanol is a chemical compound that is produced in small amounts within the small intestine and is also ingested from alcoholic drinks. Ethanol's digestion involves a complex catabolic pathway that mainly takes place in the liver. Ethanol is turned into acetaldehyde, then to acetate, and finally into acetyl-CoA. Ethanol Metabolism

  • There are multiple pathways, but the major one is the acetaldehyde pathway:
    • Acetaldehyde and reduced nicotinamide adenine dinucleotide (NAD+) are generated.
    • Acetaldehyde is metabolized to acetate by acetaldehyde dehydrogenase.
    • Acetaldehyde dehydrogenase has multiple isoforms with different levels of activity.
    • Accumulation of acetaldehyde is 1 factor responsible for liver injury.
  • With excessive alcohol consumption, microsomal cytochrome P450 plays a role in metabolism:
    • Reactive oxygen species are formed in this pathway.
    • Contribute to oxidative damage in alcoholic liver disease
  • Alcohol metabolism causes:
    • Relative hypoxia in liver zone III (near central veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins; poorly oxygenated) > zone I (around the portal tracts where oxygenated blood enters)
    • Necrosis and hepatic vein sclerosis
  • Alcohol increases intestinal permeability:
    • Bacterial translocation
    • Elevated levels of endotoxin in blood
    • Endotoxin causes inflammatory cytokine activation and contributes to inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of liver parenchyma.

Histopathological changes

  • Steatosis stage:
    • Increased NAD+ decreases ATP supply to the liver impairing lipolysis.
    • Fatty acids Fatty acids Fatty acids are integral building blocks of lipids, and can be classified as unsaturated or saturated based on the presence/absence of carbon-carbon double bonds within their nonpolar chains. Fatty Acids and Lipids and triglycerides accumulate in the liver.
    • Swollen hepatocytes (macrovesicules)
    • Fat infiltration in hepatocytes close to the venules
    • Can develop within 2 days of excess ethanol consumption
    • Resolves within 2 weeks of discontinuation of alcohol
  • Hepatitis stage:
    • Generation of inflammatory cytokines
    • Lobular infiltration of PMN
    • Ballooning degeneration of hepatocytes
    • Mallory bodies (intracellular eosinophilic aggregates representing hyaline deposits)
    • Hepatocellular necrosis
    • Inflammation leads to activation of stellate cells and pericellular fibrosis.
  • Cirrhosis stage:
    • Perivenular fibrosis (collagen deposition near the hepatic vein and sinusoid)
    • Continuous injury and regeneration lead to regenerative nodule formation.
    • Damage is usually irreversible.
    • Progressive fibrosis leads to obstruction of normal portal blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure and development of portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension.
Progression of alcoholic liver disease

Progression of liver damage in alcoholic liver disease (left to right):
1. Healthy hepatocytes (no liver damage)
2. Bloated hepatocytes with steatosis (distended by fat droplets), no inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation: steatosis (liver damage still reversible)
3. Inflamed and dying hepatocytes, possible fibrosis: hepatitis (liver damage still reversible)
4. Dead cells: cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis (irreversible liver damage)

Image by Lecturio.

Clinical Presentation

Alcoholic steatosis (fatty liver)

  • Asymptomatic
  • May have vague abdominal discomfort
  • Hepatomegaly on examination

Alcoholic hepatitis

  • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Loss of appetite, nausea
  • RUQ discomfort
  • Jaundice
  • Hepatomegaly
  • Portal hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Lethargy, confusion (from hepatic encephalopathy Hepatic Encephalopathy Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. Hepatic Encephalopathy)

Alcoholic cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis

  • Fatigue, malaise
  • Weight loss
  • Jaundice and scleral icterus (from hyperbilirubinemia)
  • Pruritus (bile salt deposition in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)
  • Hepatic encephalopathy:
    • Asterixis
    • Lethargy
    • Confusion
    • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • Ascites (due to portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension and decreased albumin)
  • Upper GI bleeding (esophageal varices from portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension)
  • Skin changes:
    • Telangiectasias 
    • Caput medusae (dilation of periumbilical veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins
    • Peripheral palmar erythema
    • Clubbed nails
  • Dupuytren’s contracture (flexion deformities of fingers from thickening and shortening of palmar fascia)
  • Hyperestrogenism:
    • Gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia
    • Hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism (testicular atrophy)
    • Reduced libido 
    • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction 
    • Infertility 
    • Amenorrhea
  • Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia
  • Smooth tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue due to 1 or more nutritional deficiencies (iron, folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12, vitamin B12)

Diagnosis and Severity Scores

History

  • Alcohol consumption (duration, quantity, and frequency)
  • Inquire about other potential causes:
    • Hereditary disorders (hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency)
    • Viral hepatitis (IV drug use)
    • Medications (e.g., acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen overuse)
  • Constitutional symptoms:
    • Fever, malaise
    • Weight loss
    • Anorexia
  • GI symptoms:
    • RUQ pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Nausea/vomiting
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea

Physical exam

  • General:
    • Jaundice, scleral icterus
    • Characteristic cirrhotic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin changes
  • Abdominal:
    • Hepato- or splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
    • Abdominal distention (from ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites)
    • RUQ tenderness

Laboratory studies

  • Alcoholic fatty liver disease:
    • ↑ AST > ↑ ALT
    • ↑ GGT (gamma glutamyl transferase)
  • Alcoholic hepatitis:
    • AST/ALT ratio > 2: a very specific marker of alcoholic liver disease
    • AST or ALT < 500
    • ↑ Alkaline phosphatase (ALP) and GGT
    • ↑ Bilirubin
    • ↓ Albumin
    • ↑ PT, INR, and PTT 
    • Macrocytic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Neutrophilic leukocytosis 
  • Alcoholic cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis:
    • ↑ AST > ALT: usually modest elevation 
    • ↑ Bilirubin 
    • ↑ GGT
    • ↑ ALP (< 2–3x the normal value)
    • ↑ Ammonia 
    • ↓ Total protein (↓ albumin)
    • ↑ PT
    • Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets
    • Anemia
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia

Imaging

  • Ultrasound:
    • Steatosis:
      • Hepatomegaly
      • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver echogenicity
    • Hepatitis:
      • Diffuse echogenicity due to increased fat deposition
      • Hepatomegaly
      • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema near the portal triad
    • Cirrhosis:
      • Echogenicity with irregular areas
      • Atrophy of right lobe
      • Hypertrophy of left and caudate lobes
      • Shrunken nodular liver in advanced cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
      • Ascites
  • CT scan:
    • Provides the same information as ultrasound
    • May show nodular liver, right-lobe atrophy, left-lobe hypertrophy, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
    • Good for ruling out hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases ( HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases)
Subacute bacterial empyema ct scan showing cirrhosis

Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis with concomitant empyema (asterisk and arrows):
Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver appears nodular, irregular, and shrunken (notice abdominal ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites).

Image: “Subacute bacterial empyema” by Department of Pulmonary Medicine, Institute of Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and Biliary Sciences, New Delhi, India. License: CC BY 4.0

Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver biopsy

  • Gold standard for cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Not necessary if convincing clinical picture and laboratory studies
  • Can be done with a percutaneous, transjugular, or laparoscopic approach

Disease severity scores

Maddrey discriminant function:

  • Estimates disease severity and mortality risk for alcoholic hepatitis
  • Calculated from serum bilirubin and PT
  • Discriminant function ≥ 32:
    • High short-term mortality
    • May benefit from glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids

Glasgow alcoholic hepatitis score:

  • Based on age, serum bilirubin, BUN, PT, and WBC count
  • Glasgow alcoholic hepatitis score ≥ 9 is predictive of mortality. 

Model for End-Stage Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver Disease score:

  • Predicts survival in cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, but can also be used for alcoholic hepatitis.
  • Based on serum bilirubin, creatinine, INR, and serum Na
  • Scale range: 6–40

Management

Hepatic stenosis

  • Alcohol cessation
  • Healthy diet

Alcoholic hepatitis

Mild-to-moderate hepatitis:

  • Alcohol cessation:
    • Disulfiram, naltrexone, acamprosate
    • Referral to Alcoholics Anonymous
  • Hydration and electrolyte correction
  • Nutritional supplementation (especially thiamine)
  • Treat any concomitant hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus ( HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus) or HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus infection.

Severe hepatitis:

  • Model for End-Stage Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver Disease score > 21
  • Measures used for mild-to-moderate hepatitis + pharmacological therapy:
    • Glucocorticoids:
      • Prednisolone
      • Aim is to reduce inflammatory changes in hepatocytes.
    • Pentoxifylline (for patients with contraindications to steroids):
      • Active GI bleed
      • Severe pancreatitis 
      • Active infection
      • Renal failure
Approach and management algorithm for alcoholic hepatitis

Management algorithm or alcoholic hepatitis

Image by Lecturio.

Cirrhosis

  • Supportive management similar to alcoholic hepatitis
  • Esophageal varices:
    • Patients should get screened with upper endoscopy.
    • Prophylaxis of bleeding is aimed at reducing portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension:
      • Beta-blockers
      • Transjugular intrahepatic shunts
  • Symptomatic management of ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites:
    • Salt restriction, water restriction
    • Diuretics
    • Therapeutic paracentesis
  • Hepatic encephalopathy:
    • Restrict protein intake.
    • Oral lactulose
    • Oral neomycin
  • Surveillance for HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver transplant is indicated for:
    • Failure of medical management
    • Model for End-Stage Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver Disease score > 20
    • Only for patients who have been abstinent

Prognosis

  • 10%–20% of patients with alcoholic hepatitis progress to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis every year.
  • 10% of individuals with alcoholic hepatitis regress with abstinence.
  • Median survival for compensated cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis (without complications) is > 12 years.
  • Median survival in cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis with Model for End-Stage Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver Disease score ≥ 21 is ≤ 6 months.

Differential Diagnosis

  • Non-alcoholic fatty liver disease: presents with findings similar to steatohepatitis (the same lab results and clinical presentation). A distinction between alcoholic and non-alcoholic fatty liver disease can only be drawn based on patient history. Diagnosis is established based on clinical presentation and laboratory studies. Treatment is focused on lifestyle modifications.
  • Viral hepatitis: infection from a virus causing acute liver disease. Presentation includes jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever with hepatomegaly, and transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids elevation often > 500. Further differentiation can be established by detecting viral antigens and antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins in the serum. Treatment is based on the cause; certain types can be prevented by vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination
  • Autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis: acute liver failure presenting with fatigue, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly, and RUQ tenderness. Drug-induced hepatitis must be ruled out by history and laboratory evaluation. The presence of an anti-smooth muscle antibody is a strong indicator of autoimmune hepatitis. The patient is treated with immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants
  • Other causes of hepatitis (drug-induced): jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly, and RUQ discomfort present after ingestion of a hepatotoxic drug. Injury can be hepatocellular (elevated transaminases) and/or cholestatic (elevated ALP). Treatment is the removal of the offending drug.

References

  1. Goldberg E., Chopra S. (2021). Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis. Retrieved February 23, 2021, from https://www.uptodate.com/contents/cirrhosis-in-adults-etiologies-clinical-manifestations-and-diagnosis
  2. Scott L Freidman. (2020). Alcoholic hepatitis: Clinical manifestations and diagnosis. UpToDate. Retrieved February 19, 2021, from https://www.uptodate.com/contents/alcoholic-hepatitis-clinical-manifestations-and-diagnosis
  3. Scott L Freidman. (2020). Management and prognosis of alcoholic hepatitis. UpToDate. Retrieved February 10, 2021, from https://www.uptodate.com/contents/management-and-prognosis-of-alcoholic-hepatitis
  4. Patel R, Mueller M. (2020). Alcoholic Liver Disease. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK546632/
  5. Woodley M, Whelan A. (1992). Manual of Medical Therapeutics. 27th Edition; p. 309–322.

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