| Alcoholic hepatitis | |
|---|---|
 | |
| Micrograph showing aMallory body, ahistopathologic finding associated with alcoholic hepatitis.H&E stain. | |
| Specialty | Gastroenterology |
| Complications | Cirrhosis, kidney failure, confusion, drowsiness and slurred speech (hepatic encephalopathy), ascites, enlarged veins (varices)[1] |
| Risk factors | Sex, obesity, genetic factors, race and ethnicity, binge drinking[1] |
Alcoholic hepatitis ishepatitis (inflammation of theliver) due to excessive intake ofalcohol.[2] Patients typically have a history of at least 10 years of heavy alcohol intake, typically 8–10 drinks per day.[3] It is usually found in association withfatty liver, an early stage ofalcoholic liver disease, and may contribute to the progression of fibrosis, leading tocirrhosis. Symptoms may present acutely after a large amount of alcoholic intake in a short time period, or after years of excess alcohol intake. Signs and symptoms of alcoholic hepatitis includejaundice (yellowing of the skin and eyes),ascites (fluid accumulation in theabdominal cavity),fatigue andhepatic encephalopathy (brain dysfunction due toliver failure).[3] Mild cases are self-limiting, but severe cases have a high risk ofdeath. Severity in alcoholic hepatitis is determined several clinical prediction models such as theMaddrey's Discriminant Function and theMELD score.
Severe cases may be treated withglucocorticoids with a response rate of about 60%. The condition often comes on suddenly and may progress in severity very rapidly.
Alcoholic hepatitis is characterized by a number of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen (ascites), and modest elevation of liverenzyme levels (as determined byliver function tests).[4] It may also present withHepatic encephalopathy (brain dysfunction due to liver failure) causing symptoms such as confusion, decreased levels of consciousness, orasterixis,[5] (a characteristic flapping movement when the wrist is extended indicative of hepatic encephalopathy). Severe cases are characterized by profound acute onset jaundice,obtundation (ranging from drowsiness to unconsciousness), and progressive critical illness; the mortality rate is 50% within 30 days of onset despite best care.[3]
Patients with alcoholic hepatitis can also present withalcohol withdrawal symptoms secondary to abstaining from alcohol in the setting of alcohol dependence.[6] Alcohol withdrawal symptoms can include tremors, tachycardia, and progress to seizures or delirium in severe withdrawal.[6] Similarly, patients with alcoholic hepatitis can present with long-term effects of alcohol in heavy, chronic alcohol users like Dupuytren contraction and temporal muscle wasting.[6]
Alcoholic hepatitis is distinct from cirrhosis caused by long-term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholiccirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption.[7] Patients with alcoholic hepatitis and concomitant cirrhosis may present with cirrhosis stigmata like jaundice, palmar erythema, spider angiomata.[6] Some alcoholics develop acute hepatitis as an inflammatory reaction to the cells affected byfatty change.[7] This is not directly related to the dose of alcohol. Some people seem more prone to this reaction than others. This inflammatory reaction to the fatty change is called alcoholicsteatohepatitis and the inflammation probably predisposes to liverfibrosis by activatinghepatic stellate cells to produce collagen.[7]
The pathological mechanisms in alcoholic hepatitis are incompletely understood but a combination of directhepatocyte damage by alcohol and its metabolites in addition to increased intestinal permeability are thought to play a role.[8] Heavy alcohol consumption increases intestinal permeability by causing direct damage toenterocytes (intestinal absorptive cells) and causing disruptions oftight junctions that form a barrier between the enterocytes.[8] This leads to increased intestinal permeability which then leads to pathogenic gut bacteria (such asenterococcus faecalis) or immunogenic fungi entering theportal circulation, and travelling to the liver where they causehepatocyte damage.[8] In the case of enterococcus faecalis, the bacterium can release anexotoxin which is directly damaging to liver cells.[8] Chronic alcohol consumption may alter the gut microbiome and promote the production of these pathogenic bacteria.[8] Many of these pathogenic bacteria also containPathogen Associated Molecular Patterns (PAMPs), extracellular motifs that are recognized by the immune system as foreign material, which may lead to an exaggerated inflammatory response in the liver which further leads to hepatocyte damage.[8]
Alcohol is also directly damaging to liver cells. Alcohol is metabolized toacetaldehyde in the liver via the enzymesCYP2E1 andaldehyde dehydrogenase.[8] Acetaldehyde formsreactive oxygen species in the liver as well as acting as aDNA adduct (binding to DNA) leading to direct hepatocyte damage.[8] This manifests aslipid peroxidation,mitochondrial damage, andglutathione (an endogenous antioxidant) depletion.[8] Damaged hepatocytes releaseDanger associated molecular patterns (DAMPs) which are molecules that lead to further activation of the immune system's inflammatory response and further hepatocyte damage.[8]
The chronic inflammation seen in alcoholic hepatitis leads to a distinctivefibrotic response, with fibrogenic cell type activation. This occurs via an increased extracellular matrix deposition around hepatocytes andsinusoidal cells which causes a peri-cellular fibrosis known as "chickenwire fibrosis".[8] This peri-cellular chickenwire fibrosis leads toportal hypertension or an elevated blood pressure in theportal veins that drain blood from the intestines to the liver.[8] This causes many of the sequelae of chronic liver disease includingesophageal varices (with associated variceal bleeding),ascites andsplenomegaly.
The chronic inflammation seen in alcoholic hepatitis also leads to impaired hepatocyte differentiation, impairments in hepatocyte regeneration and hepatocyte de-differentiation intocholangiocyte type cells.[8] This leads to defects in the liver's many functions including impairments in bilirubin transport,clotting factor synthesis, glucose metabolism and immune dysfunction.[8] This impaired compensatory liver regenerative response further leads to a ductular reaction; a type of abnormal liver cell architecture.[8]
Due to the release ofDAMPs andPAMPs, an acute systemic inflammatory state can develop after extensive alcohol intake that dominates the clinical landscape of acute severe alcoholic hepatitis.IL-6 has been shown to have the most robust increase among pro-inflammatory mediators in these patients. Furthermore, decreased levels ofIL-13, an antagonistic cytokine ofIL-6 was found to be closely associated with short-term (90-day) mortality in severe alcoholic hepatitis patients.[9]
Some signs and pathological changes in liver histology include:
If chronic liver disease is also present:
The diagnosis of alcoholic hepatitis is largely a clinical diagnosis and can be classified into three categories: Definite, Probable, and Possible alcoholic hepatitis.[14] A patient with definite alcoholic hepatitis will fulfill clinical diagnostic criteria and present with a convincing history of chronic alcohol usage and a confirmatory liver biopsy.[14] Patients with probable alcoholic hepatitis will meet clinical diagnostic criteria without the influence of confounding factors, and those with possible alcoholic hepatitis will present with a clinical diagnosis influenced by confounding factors.[14] Confounding factors to consider in this patient population include an unclear history of alcohol usage, conflicting lab results, and clinical comorbidities that may cause liver disease like Drug-indiced liver injury, infection, and viral, hepatitis.[14]
Clinical suspicion of alcoholic hepatitis should be considered in patients with a history of significant chronic alcohol intake who develops worseningliver function tests, and onset of jaundice within the last 8 weeks.[3] Additional inclusion criteria for alcoholic hepatitis includes a history of 6 months or more of continued alcohol intake, specifically >40 (female) or 60 (males) g alcohol/day, in patients who develop jaundice within less than 60 days of abstinence.[15]
Initial diagnostic work-up includes ordering routine labs and imaging including: liver function tests, complete blood count, basic metabolic panel, and a right upper quadrant ultrasound.[16][17] The liver function tests will often result in elevatedtotal bilirubin (typically greater than 3.0 mg/dL), aminotransferases that do not exceed 400 IU/L, and anaspartate aminotransferase toalanine aminotransferase ratio of usually 2 or more.[3][18][19] A CBC may be ordered to assess for acute inflammatory responses (presenting as leukocytosis and or thrombocytosis) and signs of toxic alcoholic effects on the liver and bone marrow (presenting as thrombocytopenia and or macrocytic anemia).[16][17] A BMP may be helpful to evaluate for a concomitant acute kidney injury and hepatorenal syndrome.[16][17] Furthermore, a RUQ ultrasound can help confirm the diagnosis of alcoholic hepatitis if the patient presents with findings suggestive of hepatic steatosis, hepatomegaly, and or cirrhosis.[16][17] The RUQ ultrasound is also a helpful diagnostic tool used to rule out similarly presenting hepatic pathologies like gallstones and hepatocellular carinoma.[16][17]
Confirmatory studies include a transjugular liver biopsy. A liver biopsy is not required for the diagnosis, however it can help confirm alcoholic hepatitis as the cause of the hepatitis if the diagnosis is unclear.[3][20] In patients presenting with an unclear history of alcohol consumption and confounding factors, a transjugular liver biopsy may be helpful to clarify clinical management.
The management of alcoholic hepatitis is aims to stabilize the acute on chronic liver injury to prevent further sequelae of the condition. The most important intervention to promote recovery is encouraging the patient to discontinue alcohol consumption. Abstinence from alcohol is pivotal to prevent further progression into more severe liver pathologies like alcoholic-cirrhosis or hepatocellular carcinoma.[21] This patient population by definition also presents with a chronic history of alcohol usage, so these patients should be monitored for symptoms associated with alcoholic withdrawal syndrome and undergo a CIWA-Ar screening.[22] Patients should be managed accordingly with Long or Short acting Benzodiazepines depending on their clinical comorbidities and specific presentation of withdrawal symptoms.[23][24] In addition to managing their withdrawal symptoms, these patients should also be offered counseling services to prevent relapses and further liver damage.[23]
Chronic alcohol users are also at risk for malnutrition secondary to protein and calorie deficiencies. Patients with alcoholic hepatitis commonly present with these nutritional deficiencies so it is important to perform a throughout history and physical exam to clinically correlate findings.[25][26] Additionally, the patient may also benefit from the aid of a dietician for nutritional support because malnutrition negatively affects these patient’s clinical outcomes.[25][26] Improved nutrition has been shown to improve liver function and reduce incidences encephalopathy and infections.[4][5] Current clinical guidelines recommend daily intake of 1.2-1.5 g/kg of protein and 35-40 kcal/kg of calories for patients suffering from alcoholic hepatitis.[26]
Pharmacologic interventions for alcoholic hepatitis mainly consist on the use of corticosteroids.[27] Indications for corticosteroids are based on prognostic scoring models like the MELD score andmodified Maddrey's discriminant function (MDF).[21] High scores (MELD > 20 or MDF >32) and or evidence of hepatic encephalopathy indicate the patient is suffering from severe alcoholic hepatitis and thus requires corticosteroids for acute stabilization of their condition.[21][27][28] Clinical guidelines recommend using the MELD score over the MDF as it offers better predictions of the patient’s mortality in the setting of liver failure.[28] Furthermore, theLille Model is another prognostic tool used to monitor for the patient’s response to corticosteroid treatment.[29] A Lille score > 0.45 indicates an inadequate response to treatment and entails transitioning to palliative care or enrolling the patient for an early liver transplantation. Patients scoring below 0.45 should be treated with the standard corticosteroid regimen.[29] Generally, alcoholic hepatitis patients who require corticosteroids are started onprednisolone for a month, followed by a two week taper.[27] Alternative corticosteroids include off-label IV Methlyprednisolone.[26][27]
Other pharmacologic interventions include usage of IV N-acetlycystine and previouslyPentoxifylline. IntravenousN-acetylcysteine, when used in conjunction with corticosteroids, improves survival at 28 days by decreasing rates of infection and hepatorenal syndrome.[4] Systematic reviews comparing the treatment of pentoxifylline with corticosteroids show there is no benefit to treatment with pentoxifylline.[4] Potential for combined therapy: A large prospective study of over 1000 patients investigated whether prednisolone and pentoxifylline produced benefits when used alone or in combination.[30] Pentoxifylline did not improve survival alone or in combination.[30] Prednisolone gave a small reduction in mortality at 28 days but this did not reach significance, and there were no improvements in outcomes at 90 days or 1 year.[4]
Last-line therapy involves liver transplantation. Early liver transplantation is ideal and helps to save lives.[31][32] Early liver transplantation should be recommended to patients who do not respond to medical management. This may be evident through a high Lille score or patients who further decompensate and develop complications of alcoholic hepatitis. Patients who clinically qualify for a liver transplantation should be evaluated by a transplant committee to determine if they are good candidates.[33] Most transplant providers in theUnited States require a period of alcohol abstinence (typically six months) prior to transplant, but the ethics and science behind this are controversial.[32]
The patient’s disposition is also important to consider throughout their care. If a patient with alcoholic hepatitis exhibits evidence of infection, hemodynamic instability, sepsis, signs of hepatic encephalopathy, and or extra-hepatic organ failure, they should be transferred to the ICU.[34] Patients who improve with corticosteroid therapy can be discharged with counseling resources to encourage abstinence and avoid relapses.
Patients with alcoholic hepatitis can develop infections, acute kidney injuries that may lead to hepatorenal syndrome, and cirrhosis complications. If there is clinical suspicion of infection in the setting of alcoholic hepatitis, it is important to screen for sepsis SIRS criteria and order blood cultures. If sepsis is confirmed, the patient should be immediately transferred to the ICU for high level of care.[34] Similarly, to avoid kidney complications, preferably elect to manage the patient with non-nephrotoxic medications when and if necessary.[33] Additionally, use diuretics sparingly to avoid causing or exacerbating the patients acute kidney injury.[33]
Females are more susceptible to alcohol-associated liver injury and are therefore at higher risk of alcohol-associated hepatitis.[8] Certain genetic variations in thePNPLA3-encoding gene, which codes for an enzyme involved intriglyceride metabolism inadipose tissue are thought to influence disease severity.[8] Other factors in alcoholic hepatitis associated with a poor prognosis include concomitanthepatic encephalopathy andacute kidney injury.[8]
