Alcoholic hepatitis

Alcoholic hepatitis is hepatitis (inflammation of the liver) due to excessive intake of alcohol.<ref>Template:Cite web</ref> Patients typically have a history of at least 10 years of heavy alcohol intake, typically 8–10 drinks per day.<ref name=":0">Template:Cite journal</ref> It is usually found in association with fatty liver, an early stage of alcoholic liver disease, and may contribute to the progression of fibrosis, leading to cirrhosis. 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 include jaundice (yellowing of the skin and eyes), ascites (fluid accumulation in the abdominal cavity), fatigue and hepatic encephalopathy (brain dysfunction due to liver failure).<ref name=":0" /> Mild cases are self-limiting, but severe cases have a high risk of death. Severity in alcoholic hepatitis is determined several clinical prediction models such as the Maddrey's Discriminant Function and the MELD score.

Severe cases may be treated with glucocorticoids with a response rate of about 60%. The condition often comes on suddenly and may progress in severity very rapidly.

Signs and symptoms

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 liver enzyme levels (as determined by liver function tests).<ref name=":6" /> It may also present with Hepatic encephalopathy (brain dysfunction due to liver failure) causing symptoms such as confusion, decreased levels of consciousness, or asterixis,<ref name=":1">Template:Cite journal</ref> (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.<ref name=":0" />

Patients with alcoholic hepatitis can also present with alcohol withdrawal symptoms secondary to abstaining from alcohol in the setting of alcohol dependence. <ref name=":8">Template:Cite journal</ref> Alcohol withdrawal symptoms can include tremors, tachycardia, and progress to seizures or delirium in severe withdrawal. <ref name=":8" /> 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.<ref name=":8" />

Alcoholic hepatitis is distinct from cirrhosis caused by long-term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption.<ref name="robspath" /> Patients with alcoholic hepatitis and concomitant cirrhosis may present with cirrhosis stigmata like jaundice, palmar erythema, spider angiomata.<ref name=":8" /> Some alcoholics develop acute hepatitis as an inflammatory reaction to the cells affected by fatty change.<ref name="robspath" /> 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 alcoholic steatohepatitis and the inflammation probably predisposes to liver fibrosis by activating hepatic stellate cells to produce collagen.<ref name="robspath" />

File:Depiction of a liver failure patient.png

Depiction of a liver failure patient

Pathophysiology

The pathological mechanisms in alcoholic hepatitis are incompletely understood but a combination of direct hepatocyte damage by alcohol and its metabolites in addition to increased intestinal permeability are thought to play a role.<ref name="NEJM Bataller">Template:Cite journal</ref> Heavy alcohol consumption increases intestinal permeability by causing direct damage to enterocytes (intestinal absorptive cells) and causing disruptions of tight junctions that form a barrier between the enterocytes.<ref name="NEJM Bataller" /> This leads to increased intestinal permeability which then leads to pathogenic gut bacteria (such as enterococcus faecalis) or immunogenic fungi entering the portal circulation, and travelling to the liver where they cause hepatocyte damage.<ref name="NEJM Bataller" /> In the case of enterococcus faecalis, the bacterium can release an exotoxin which is directly damaging to liver cells.<ref name="NEJM Bataller" /> Chronic alcohol consumption may alter the gut microbiome and promote the production of these pathogenic bacteria.<ref name="NEJM Bataller" /> Many of these pathogenic bacteria also contain Pathogen 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.<ref name="NEJM Bataller" />

Alcohol is also directly damaging to liver cells. Alcohol is metabolized to acetaldehyde in the liver via the enzymes CYP2E1 and aldehyde dehydrogenase.<ref name="NEJM Bataller" /> Acetaldehyde forms reactive oxygen species in the liver as well as acting as a DNA adduct (binding to DNA) leading to direct hepatocyte damage.<ref name="NEJM Bataller" /> This manifests as lipid peroxidation, mitochondrial damage, and glutathione (an endogenous antioxidant) depletion.<ref name="NEJM Bataller" /> Damaged hepatocytes release Danger associated molecular patterns (DAMPs) which are molecules that lead to further activation of the immune system's inflammatory response and further hepatocyte damage.<ref name="NEJM Bataller" />

The chronic inflammation seen in alcoholic hepatitis leads to a distinctive fibrotic response, with fibrogenic cell type activation. This occurs via an increased extracellular matrix deposition around hepatocytes and sinusoidal cells which causes a peri-cellular fibrosis known as "chickenwire fibrosis".<ref name="NEJM Bataller" /> This peri-cellular chickenwire fibrosis leads to portal hypertension or an elevated blood pressure in the portal veins that drain blood from the intestines to the liver.<ref name="NEJM Bataller" /> This causes many of the sequelae of chronic liver disease including esophageal varices (with associated variceal bleeding), ascites and splenomegaly.

The chronic inflammation seen in alcoholic hepatitis also leads to impaired hepatocyte differentiation, impairments in hepatocyte regeneration and hepatocyte de-differentiation into cholangiocyte type cells.<ref name="NEJM Bataller" /> This leads to defects in the liver's many functions including impairments in bilirubin transport, clotting factor synthesis, glucose metabolism and immune dysfunction.<ref name="NEJM Bataller" /> This impaired compensatory liver regenerative response further leads to a ductular reaction; a type of abnormal liver cell architecture.<ref name="NEJM Bataller" />

Due to the release of DAMPs and PAMPs, 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 of IL-13, an antagonistic cytokine of IL-6 was found to be closely associated with short-term (90-day) mortality in severe alcoholic hepatitis patients.<ref>Template:Cite journal</ref>

Some signs and pathological changes in liver histology include:

• Mallory's hyaline body – a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.<ref name="robspath">Template:Cite book</ref>
• Ballooning degeneration – hepatocytes in the setting of alcoholic change often swell up with excess fat, water and protein; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby biliary ducts, leading to diffuse cholestasis.<ref name="robspath" />
• Inflammation – neutrophilic invasion is triggered by the necrotic changes and presence of cellular debris within the lobules. Ordinarily the amount of debris is removed by Kupffer cells, although in the setting of inflammation they become overloaded, allowing other white cells to spill into the parenchyma. These cells are particularly attracted to hepatocytes with Mallory bodies.<ref name="robspath" />

If chronic liver disease is also present:

• Fibrosis
• Cirrhosis – a progressive and permanent type of fibrotic degeneration of liver tissue.

File:Pathogenesis alcoholic liver injury.jpg

Pathogenesis alcoholic liver injury

File:Alcohol related liver disease.webm

Alcohol related liver disease

Epidemiology

• Alcoholic hepatitis occurs in approximately 1/3 of chronic alcohol drinkers.<ref>Template:Cite journal</ref>
• 10-20% of patients with alcoholic hepatitis progress to alcoholic liver cirrhosis every year.<ref name=":4">Template:Cite journal</ref>
• Patients with liver cirrhosis develop liver cancer at a rate of 1.5% per year.<ref name=":5">Template:Cite journal</ref>
• In total, 70% of those with alcoholic hepatitis will go on to develop alcoholic liver cirrhosis in their lifetimes.<ref name=":4" />
• Infection risk is elevated in patients with alcoholic hepatitis (12–26%). It increases even higher with use of corticosteroids (50%)<ref name=":2">Template:Cite journal</ref> when compared with the general population.
• Untreated alcoholic hepatitis mortality in one month of presentation may be as high as 40-50%.<ref name=":6">Template:Cite journal</ref>

Diagnosis

The diagnosis of alcoholic hepatitis is largely a clinical diagnosis and can be classified into three categories: Definite, Probable, and Possible alcoholic hepatitis.<ref name=":10">Template:Cite journal</ref> 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.<ref name=":10" /> 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.<ref name=":10" /> 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.<ref name=":10" />

Clinical suspicion of alcoholic hepatitis should be considered in patients with a history of significant chronic alcohol intake who develops worsening liver function tests, and onset of jaundice within the last 8 weeks.<ref name=":0" /> 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.<ref name=":9">Template:Cite journal</ref>

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.<ref name=":11">Template:Cite journal</ref><ref name=":12">Template:Cite journal</ref> The liver function tests will often result in elevated total bilirubin (typically greater than 3.0 mg/dL), aminotransferases that do not exceed 400 IU/L, and an aspartate aminotransferase to alanine aminotransferase ratio of usually 2 or more.<ref name=":0" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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).<ref name=":11" /><ref name=":12" /> A BMP may be helpful to evaluate for a concomitant acute kidney injury and hepatorenal syndrome.<ref name=":11" /><ref name=":12" /> 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.<ref name=":11" /><ref name=":12" /> The RUQ ultrasound is also a helpful diagnostic tool used to rule out similarly presenting hepatic pathologies like gallstones and hepatocellular carinoma.<ref name=":11" /><ref name=":12" />

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.<ref name=":0" /><ref name="AAFP Keating">Template:Cite journal</ref> In patients presenting with an unclear history of alcohol consumption and confounding factors, a transjugular liver biopsy may be helpful to clarify clinical management.

Management

Clinical practice guidelines have recommended corticosteroids.<ref name="pmid9820369">Template:Cite journal</ref>

When considering the basic principles of alcoholic hepatitis management, it is important to address the following bulleted topics:

• Abstinence: Stopping further alcohol consumption is the number one factor for recovery in patients with alcoholic hepatitis.<ref name=":3">Template:Cite journal</ref>
• Alcohol withdrawal syndrome assessment and work-up: Given that many alcoholic hepatitis patients have a history of chronic alcohol usage, it is important to consider alcohol withdrawal syndrome with a Clinical institute withdrawal assessment for alcohol, revised (CIWA-Ar).<ref>Template:Cite journal</ref> For patients who develop alcohol withdrawal complications, first line pharmacologic therapy includes long acting benzodiazepines like Chloradiazepine and Diazepam.<ref name=":13">Template:Cite journal</ref><ref name=":14">Template:Cite journal</ref> Consider short acting benzodiazepines like Oxazepam or Lorazepam in the elderly and patients with liver failure. It is also important to provide the patient with counseling services to help prevent future alcohol intake and or relapses.<ref name=":13" /><ref name=":14" />
• Nutrition Supplementation: Protein and calorie deficiencies are seen frequently in patients with alcoholic hepatitis, and it negatively affects their outcomes. Improved nutrition has been shown to improve liver function and reduce incidences encephalopathy and infections.<ref name=":6" /> To prevent malnutrition in this patient population, it is important to perform a thorough history and physical exam to assess for nutritional deficiencies and even consider a consulting a dietician for additional nutritional support.<ref name=":15">Template:Cite journal</ref> Current clinical guidelines recommend a daily intake of 1.2-1.5 g/kg of protein and 35-40 kcal/kg of calories for patients suffering from alcoholic hepatitis.<ref name=":15" />
• Corticosteroids: These guidelines suggest that patients with a modified Maddrey's discriminant function score > 32 or hepatic encephalopathy should be considered for treatment with prednisolone 40 mg daily for four weeks followed by a taper.<ref name="pmid9820369" /> Patients may also receive off-label Methlyprendnisolone 32 mg IV once daily as an alternative to prednisolone therapy.<ref>Template:Cite journal</ref> Models such as the Lille Model can be used to monitor for improvement or to consider alternative treatment.
• Pentoxifylline: Systematic reviews comparing the treatment of pentoxifylline with corticosteroids show there is no benefit to treatment with pentoxifylline<ref name=":6" /> 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.<ref name="pmid25901427">Template:Cite journal</ref> Pentoxifylline did not improve survival alone or in combination. 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.<ref name=":6" />
• Intravenous N-acetylcysteine: When used in conjunction with corticosteroids, improves survival at 28 days by decreasing rates of infection and hepatorenal syndrome.<ref name=":6" />
• ICU Transfers: Alcoholic hepatitis patients with hemodynamic instability, sepsis, signs of hepatic encephalopathy, and or extra-hepatic organ failure should be transferred to the ICU.<ref name=":17">Template:Cite journal</ref>
• Liver Transplantation: Early liver transplantation is ideal and helps to save lives.<ref name=":7">Template:Cite journal</ref> Early liver transplantation should be considered in patients who do not respond well to medical therapy and are cleared by a multidisciplinary transplant team.<ref>Template:Cite journal</ref> Most transplant providers in the United States require a period of alcohol abstinence (typically six months) prior to transplant, but the ethics and science behind this are controversial.<ref name=":7" />

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.<ref name=":17" /> Similarly, to avoid kidney complications, preferably elect to manage the patient with non-nephrotoxic medications when and if necessary.<ref name=":18">Template:Cite journal</ref> Additionally, use diuretics sparingly to avoid causing or exacerbating the patients acute kidney injury.<ref name=":18" />

People should be risk stratified using a MELD Score, modified Maddrey's discriminant function score, or Lille Model. These scores are used to evaluate the severity of the liver disease based on several lab values. The greater the score, the more severe the disease.

• The MELD Score or Model for End-Stage Liver Disease is the most favored prognostic scoring model used to direct management of alcoholic hepatitis.<ref name=":19">Template:Cite journal</ref> The MELD score offers a insight into the patients' predicted mortality in the setting of liver failure.<ref name=":19" /> Patients with MELD scores above 20 are considered to have severe alcoholic hepatitis and thus have a 20% chance of dying within 90 days.<ref name=":19" /> Patients scoring higher than a MELD of 20 should be started on corticosteroid regimen.<ref name=":19" />

• The Lille Model is useful for monitoring the patients' response to medical management of alcoholic hepatitis. A lille score of greater than 0.45 suggests an inadequate patient response while a score below 0.45 indicates an adequate response to corticosteroid therapy.<ref name=":16">Template:Cite journal</ref> In cases in which the patient scores above than 0.45, clinical guidelines recommend seeking alternative therapy options in the from of supportive or palliative care, and even early liver transplantation.<ref name=":16" /> Patients scoring below 0.45 should be treated with the standard 4 week corticosteroid regimen followed by a 2-4 week taper as mentioned above.<ref name=":16" />
• The modified Maddrey's discriminant function model has fallen out of favor with regards to assessing mortality of patients with alcoholic hepatitis. Although it was primary used in the past, clinical guidelines now recommend usage of the MELD score for prognostic scoring. However, patients scoring above a 32 on the modified Maddrey's discriminant function are considered to have severe alcoholic hepatitis and should be started on steroid treatment.<ref name="pmid9820369" />

Prognosis

Females are more susceptible to alcohol-associated liver injury and are therefore at higher risk of alcohol-associated hepatitis.<ref name="NEJM Bataller" /> Certain genetic variations in the PNPLA3-encoding gene, which codes for an enzyme involved in triglyceride metabolism in adipose tissue are thought to influence disease severity.<ref name="NEJM Bataller" /> Other factors in alcoholic hepatitis associated with a poor prognosis include concomitant hepatic encephalopathy and acute kidney injury.<ref name="NEJM Bataller" />

See also

• AST/ALT ratio
• Lille Model
• Steatohepatitis