Alcoholic Fatty Liver; Causes, Symptoms, Diagnosis, Treatment

Alcoholic Fatty Liver/Alcoholic Liver Disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, maybe as high as 20–50% at 1 month.

Alcoholic liver disease (ALD) is one of the major medical complications of alcohol abuse. Alcohol is the major cause of liver cirrhosis in the Western world, with schistosomal infection being the major cause of portal hypertension in developing countries. Alcohol accounts for 80% of all liver cirrhosis cases seen in district general hospitals in the UK. Alcoholic cirrhosis is increasingly seen in countries such as Japan and India which traditionally had a low prevalence of the disease.

Types of Alcoholic Liver Disease

There are three histologic stages of alcoholic liver disease[rx][rx]:

• Alcoholic fatty liver or steatosis – At this stage, fat accumulates in the liver parenchyma.
• Alcoholic hepatitis – Inflammation of liver cells takes place at this stage, and the outcome depends on the severity of the damage. Alcohol abstinence, nutritional support, treatment of infection, and prednisolone therapy in severe cases can help in the treatment of alcoholic hepatitis, but more severe cases lead to liver failure.
• Alcoholic cirrhosis – Liver damage at this stage is irreversible and leads to complications of cirrhosis and portal hypertension.

Pathophysiology

Alcohol undergoes an oxidative metabolic pathway in the hepatocytes, leading to a reduced ratio of the nicotinamide adenine dinucleotide (NAD) to NADH. This promotes lipogenesis by inhibiting oxidation of triglyceride and fatty acids. Another known mechanism of alcohol-induced liver injury is the translocation of endotoxins in the form of lipopolysaccharides (LPS), from the intestines into the hepatocytes. In the hepatic Kupffer cells, the LPS binds to CD 14 and toll-like receptor 4 to release a barrage of reactive oxygen species (ROS). The ROS activates the release of cytokines such as tumor necrosis factor-alpha (TNF alpha), interleukin-8, monocyte chemotactic protein 1 (MCP-1) and platelet-derived growth factor (PDGF), all of which leads to accumulation of neutrophils, macrophages and systemic clinical features of alcohol injury. Recent studies indicate patients with specific intestinal dysbiosis been increasingly susceptible to alcoholic liver disease and AH.

Causes of Alcoholic Liver Disease

Among problem drinkers, only about 35 percent develop advanced liver disease. This is because modifiers, as listed below, exist that exacerbate, slow, or prevent ALD disease progression.

• The pattern of Consumption and Beverage Type – The most important factors determining the progression of liver disease are the beverage type consumed and the amount and pattern of drinking (e.g., outside mealtime or binges). Intake of 40 to 80 grams ethanol/day by males and of 20 to 40 grams/day by females for 10 to 12 years is a general predictor of more severe cases of ALD, including alcoholic steatohepatitis, fibrosis, and cirrhosis
• Gender – Epidemiologic data show that women are more susceptible to alcohol-related liver damage than men. This appears to be related to higher blood alcohol concentrations in women than in men who ingest the same amount of alcohol, resulting from a lower proportion of body water in females compared with males of equal weight [rx]. There also are reports that women possess a lower capacity than men to oxidize ethanol in the gut, a process called first-pass metabolism [rx]. This deficit in women allows greater quantities of ethanol into the portal circulation, thereby exposing their livers to higher ethanol concentrations. Further, gender-based differences in the sensitivity of KCs to endotoxins and hepatic inflammatory responses have been related to higher susceptibility to ALD progression in females than in males [rx].
• Age – It is not completely clear how age modifies ALD progression. It is, however, a predictor for ALD [rx], because older adults (i.e., ages 65 and up) are more vulnerable to and show greater degrees of ethanol-induced impairments than younger people [rx].
• Race/Ethnicity – Ethnicity is a major factor affecting the age and severity of the presentation of different subtypes of ALD [rx]. The reason(s) for these differences are not clear.
• Genetics – Both genetic and epigenetic influences govern the initiation and progression of ALD. Genome-wide association studies have identified specific genetic markers (i.e., single-nucleotide polymorphisms) in genes encoding alcohol-metabolizing enzymes, cytokines, and antioxidant enzymes that are related to the progression of ALD [rx]. Most recently, an allele of patatin-like phospholipase domain-containing protein 3 (PNPLA3 I148M), a triglyceride-degrading enzyme, was identified as an independent risk factor for alcoholic cirrhosis [rx].
• Nutritional Factors – Dietary fat is a macronutrient and dietary modifier for ALD. In rodents, dietary saturated fat seems to protect against alcohol-induced liver damage, whereas dietary unsaturated fat that is enriched in linoleic acid reportedly promotes such damage [rx].
• Drugs – Alcohol and other drugs (including prescription medications, over-the-counter agents, and illicit drugs) interact to enhance hepatotoxicity. For example, as described earlier, acetaminophen hepatotoxicity can be exacerbated by alcohol abuse.
• Obesity – Population-based studies have indicated a significant correlation between the risk of liver damage and alcohol consumption in people with a high body mass index [rx].
• Smoking – Cigarette smoking can adversely affect certain hepatic functions and is associated with a higher risk of alcoholic cirrhosis in humans [rx].
• Viral Infections – The course of hepatitis C (HCV) and hepatitis B (HBV) viral infections is worsened in alcohol-abusing patients, causing rapid progression to fibrosis, cirrhosis, and even hepatocellular carcinoma [rx]. Several common mechanisms of viral infection and alcohol-induced damage have been suggested [rx]; however, the exact mechanisms for this rapid disease progression are not completely understood. Because viral infections such as HCV or HBV affect more than 170 million people worldwide [rx], the following section will describe this topic in greater detail.

• Acute intoxication (apnea, aspiration of gastric content) Alcohol use disorders
• The gastrointestinal tract, pancreas, and liver
• Alcoholic liver disease
• Alcoholic pancreatitis
• Cancer of the upper digestive tract (oral cavity, pharynx, hypopharynx, pharynx, esophagus)
• Motility disorders (esophagus, gastroesophageal reflux, gastric emptying, diarrhea)
• Mucosal damage (including hemorrhagic gastritis)
• Lactose intolerance
• Colorectal cancer

Metabolic disorders

• Hypoglycemia
• Hyperlipoproteinemia
• Hyperuricemia (including gout)
• Porphyria
• Hyperferritinemia
• Fetal alcohol syndrome

Cardiovascular disease

• Cardiomyopathy
• Arrhythmia (including atrial fibrillation)
• Arterial hypertension
• Alcoholic myopathy
• Alcoholic osteopathy

Neurological and psychiatric disorders

• Peripheral neuropathy
• Dementia
• Cerebellar atrophy with dyskinesia
• Depression (including suicide)

Trauma

• Bone fractures
• Subdural hematoma
• Breast cancer

Infections

• Endocarditis
• Viral hepatitis
• Sepsis
• Tuberculosis

Skin disease

• Psoriasis
• Telangiectasias
• Spider angiomas
• Rhinophyma
• Palmar erythema
• Variceal hemorrhage
• Hepatic encephalopathy
• Coagulopathy
• Thrombocytopenia
• Ascites
• Spontaneous bacterial peritonitis
• Iron overload

Symptoms of Alcoholic Liver Disease

One should ask questions about diet, caloric intake, risk factors for malnutrition, and also about the risks for various types of chronic liver disease, including chronic viral hepatitis.

Questions about the following symptoms are necessary and informative:

• Nausea and vomiting
• Fever (in alcoholic hepatitis)
• Weakness
• Yellowish discoloration of eyes
• Loss of appetite
• Abdominal discomfort
• Increased thirst
• Weight loss
• Fainting
• Confusion
• Alteration of the sleep-wake cycle
• Mood swings
• Being unable to control alcohol consumption
• Craving alcohol when you’re not drinking
• Putting alcohol above personal responsibilities
• Feeling the need to keep drinking more
• Spending a substantial amount of money on alcohol

Diagnosis of Alcoholic Liver Disease

Evaluation should include[rx]:

• CBC (Complete blood count) – to rule out the infection, look for complications of cirrhosis: anemia, thrombocytopenia, a leukemoid reaction in alcoholic hepatitis.
• LFTs (liver function tests) – AST (aspartate aminotransferase) is markedly raised compared to ALT (alanine aminotransferase) in alcoholic liver disease, albumin is low, bilirubin is elevated. GGTP ( gamma-glutamyl transpeptidase) is usually elevated along with elevated triglyceride levels.
• Prothrombin time (PT) and INR (to assess liver synthetic function) – an elevated value indicates more severe disease.
• Abdominal imaging (abdominal ultrasonography) – is useful to look for biliary obstruction and liver tumors.
• BMP (basic metabolic profile) – should be ordered to look for renal failure and electrolyte disturbance (low levels of potassium, magnesium, and phosphorus).
• Ascitic fluid SAAG (serum-ascites albumin gradient) –  should be calculated to assess the reason for ascites if present.
• Screening blood tests –  for other causes of chronic liver disease, including viral hepatitis.
• Endoscopy to look for esophageal varices – due to portal hypertension in patients with cirrhosis.
• A liver biopsy –  can lead to a definitive diagnosis in cases where the diagnosis is uncertain. It is used more often for evaluation of severity, staging, prognosis, and treatment monitoring. At least 1.5 to 2 cm long sample of liver tissue is necessary for accurate diagnosis of fibrosis. A small sample of liver cells is taken and sent to a laboratory to be examined under a microscope. The biopsy is usually carried out under local anesthetic, either as a day case or with an overnight stay in the hospital. Your liver tissue will be examined to determine the degree of scarring in the liver and the cause of the damage.
• Endoscopy – An endoscope is a long, thin, flexible tube with a light and a video camera at one end. During an endoscopy, the instrument is passed down your esophagus (the long tube that carries food from the throat to the stomach) and into your stomach. Pictures of your esophagus and stomach are transmitted to an external screen. The doctor will be looking for swollen veins (varices), which are a sign of cirrhosis.

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Treatment of Alcoholic Liver Disease

Non-Pharmacological

Treatment and management of alcohol liver disease depend on the stage of the disease.

• Alcohol abstinence, enrollment to detoxification programs
• Abstinence – Complete abstinence from alcohol is the most important therapeutic intervention for people with Alcoholic Liver Disease. Abstinence from alcohol reduces the risk of further damage to the liver, but it also provides it with a chance to recover. Patients suffering from ALD should completely refrain from drinking, thereby improving the outcome & histological features of hepatic injury. They should give their bodies a chance to reduce portal pressure and decrease progression to cirrhosis. It eventually helps to improve survival at all ALD stages.
• Nutritional Therapy – One of the major complications of ALD is malnutrition, especially in patients who are in the second stage of alcoholic hepatitis. In patients with ALD, protein-calorie malnutrition is highly prevalent. Patients in any stage of alcoholic liver disease must consult a hepatologist and get started with nutritional therapy at earliest. It can help in alleviating the symptoms and improving the present stage of the liver.
• A diet and vitamin supplements (especially B vitamins) are important during the first few days of abstinence. They can help correct nutritional deficiencies that can cause complications such as weakness, shaking, loss of sensation and strength, anemia, and Wernicke encephalopathy. Supplements can also improve general health. Often, if inflammation is severe, people are hospitalized and may need to be fed through a tube to receive adequate nutrition.
• Counseling – A qualified counselor can help the person share their problems and then devise a plan to tackle the drinking. Cognitive-behavioral therapy (CBT) is commonly used to treat alcohol dependency.
• Treating underlying problems – There may be problems with self-esteem, stress, anxiety, depression, or other aspects of mental health. It is important to treat these problems, too, as they can increase the risks posed by alcohol. Common alcohol-related issues, such as hypertension, liver diseases, and possibly heart diseases, will need to be treated too.
• Residential programs – These can offer expert professional help, individual or group therapy, support groups, training, family involvement, activity therapy, and a host of strategies for treating alcohol abuse. Being physically away from access to temptation is helpful for some people.
• Cognitive–Behavioral Therapy – can take place one-on-one with a therapist or in small groups. This form of therapy is focused on identifying the feelings and situations (called “cues”) that lead to heavy drinking and managing stress that can lead to relapse. The goal is to change the thought processes that lead to excessive drinking and to develop the skills necessary to cope with everyday situations that might trigger problem drinking.
• Motivational Enhancement Therapy – is conducted over a short period of time to build and strengthen motivation to change drinking behavior. The therapy focuses on identifying the pros and cons of seeking treatment, forming a plan for making changes in one’s drinking, building confidence, and developing the skills needed to stick to the plan.
• Marital and Family Counseling – incorporates spouses and other family members in the treatment process and can play an important role in repairing and improving family relationships. Studies show that strong family support through family therapy increases the chances of maintaining abstinence (stopping drinking), compared with patients undergoing individual counseling.
• Brief Interventions – are short, one-on-one or small-group counseling sessions that are time-limited. The counselor provides information about the individual’s drinking pattern and potential risks. After receiving personalized feedback, the counselor will work with the client to set goals and provide ideas for helping to make a change.

Non-Pharmacological

• Corticosteroids – Corticosteroids have been the most extensively studied form of therapy for AH, but their role remains limited [rx]. The rationale for steroid use is to decrease the immune response and pro-inflammatory cytokine response. Most randomized studies have supported the use of corticosteroids in moderate/severe AH [rx],
• Pentoxifylline – Pentoxifylline (400 mg 3 times/d for 28 d) is considered as an alternative to corticosteroid treatment in patients with severe alcoholic hepatitis[rx]. The exact mechanism is not understood. However, pentoxifylline inhibits phosphodiesterase and increases the intracellular adenosine 3’,5’-cyclic monophosphate level inducing inhibition of cytokine expression and macrophage inflammatory protein-1a[rx]. Pentoxifylline failed to decrease the serum TNF-α level in the treated group in another study[rx]. The protective effect against hepatorenal syndrome appears to be the main mechanism of action against alcoholic hepatitis according to a randomized controlled study[rx].
• Anti-TNF-α therapy  – Anti-TNF-α agents have been developed to block TNF-α, a major cytokine involved in alcoholic hepatitis. Two anti-TNF-α agents have been investigated as a therapy for alcoholic hepatitis, infliximab, and etanercept. In a pilot study, combination therapy with infliximab and steroids was reported to be effective[rx]. However, the trial was stopped early by the independent data and safety monitoring board because of a significant excess of severe infections and an insignificant increase in the deaths in the infliximab cohort [rx].
• Etanercept  – showed an increase in the short-term survival of patients in a pilot study[rx]. However, a subsequent randomized, placebo-controlled trial revealed a worse 6-mo survival rate in the group treated with etanercept than in the placebo group[rx]. Therefore, anti-TNF-α agents are currently not recommended for treating alcoholic hepatitis.
• N-acetylcysteine – The combination of N-acetylcysteine, an antioxidant, with prednisolone has been studied. This study enrolled 174 patients who were randomly assigned to receive either prednisolone 40 mg/d for 28 d along with intravenous N-acetylcysteine for 5 d or prednisolone 40 mg/d for 28 d alone. Combination therapy improved the 1-mo survival in patients with alcoholic hepatitis. However, the 6-mo survival, which was the primary endpoint of the study, did not improve[rx,rx]. Further research is needed to evaluate the efficacy of N-acetylcysteine.
• Metadoxine – Metadoxine, a combination of 2 antioxidants (pyridoxine and pyrrolidone), is potentially a useful drug in the treatment of ALD. In a large randomized controlled trial, there was a significant improvement in the liver function tests in both groups. The percentage of patients with persistent hepatic steatosis as assessed by ultrasound, was also significantly lower in the methadone group (28% vs 70%)[rx]. These positive effects were more noticeable in patients who abstained from alcohol compared to those who continued to drink. However, the clinical implications are still unclear; therefore, methadone is not recommended for the treatment of ALD. Further studies are required to better explain the significance of these observations on other clinical endpoints.
• Propylthiouracil – Propylthiouracil has also been evaluated for the treatment of acute hepatitis. In some studies, PTU improved the mortality rate by suppressing hypermetabolic activation[rx,rx]. However, in a Cochrane meta-analysis of 6 studies with 710 ALD patients that compared propylthiouracil versus placebo, there was no clear improvement in the liver histology or liver-related or overall mortality rate[rx,rx].
• Colchicine – Colchicine affects hepatic fibrogenesis, including the inhibition of collagen production, the enhancement of collagenase activity, and the interference with collagen transcellular trafficking. In addition, colchicine also has favorable effects on cytokine production associated with fibroblast proliferation. In clinical studies involving patients with alcoholic liver cirrhosis, colchicine showed anti-inflammatory and anti-fibrotic effects[rx,rx], and had a positive effect on survival[rx]. However, controlled trials later had conflicting results[rx].
• Polyunsaturated lecithin – Polyunsaturated lecithin is extracted from soybeans and is a constituent of cell membranes[rx]. Polyunsaturated lecithin appears to improve histology and reduce the activation of hepatic stellate cells in baboons with alcoholic liver injury[rx]. However, polyenylphosphatidylcholine did not show a clear association with the progression of liver fibrosis in a follow-up randomized controlled study[rx].
• Angiotensin II receptor blocker – It has been reported in one randomized controlled trial that combination therapy with candesartan and ursodeoxycholic acid shows greater histologic improvement compared to monotherapy with ursodeoxycholic acid[rx].
• Silymarin – Silymarin, a milk thistle extract with anti-oxidative and anti-fibrotic properties, has been evaluated in many studies as a potential treatment agent for ALD[rx,rx]. Although one study reported that silymarin contributes to improved survival, this result has not been confirmed for ALD patients in meta-analyses such as the Cochrane review[rx,rx].
• Colchicine – Colchicine has been suggested as a treatment for ALD because of its anti-fibrotic effects. It has many potential therapeutic mechanisms of action including inhibition of collagen production, enhancement of collagenase activity, and anti-inflammatory functions. [rx] Results showed no beneficial effect on either overall mortality or liver-related mortality [rx]. A recent smaller study from Europe also showed no beneficial effects of colchicine [rx]. Thus, despite initial enthusiasm and biochemical rationale for use of this drug, it does not appear to be effective in ALD.
• Propylthiouracil (PTU) – Chronic alcohol feeding in experimental animals produces a hypermetabolic state with increased oxygen consumption. This may lead to relative hypoxia, especially in the central lobular area, or zone 3, of the liver. PTU has been postulated to attenuate this hypermetabolic state, to function as an antioxidant, and to improve portal blood flow. This prompted a long-term study of PTU therapy by Orrego et al. [rx] in over 300 patients with a variety of types of liver disease, including ALD. In the total study population, mortality was reduced by nearly 50% in patients receiving PTU [rx].
• Dilinoleoylphosphatidylcholine – Dilinoleoylphosphatidylcholine (a form of lecithin/soybean extract) has antioxidant, anti-fibrotic, and anti-cytokine activity in experimental rat models of ALD [rx]. However, a recently completed VA Cooperative Study failed to show significant benefit in human ALD [rx]. It should be noted that in that study, the partial abstinence observed in all patients, regardless of whether or not they received a placebo or drug, may have confounded any possible protective effects (see Abstinence above) [rx].
• Anabolic Steroids – ALD is associated with severe muscle wasting. While in part mediated by nutritional deficiencies, decreased functional levels of anabolic and androgenic steroids in alcoholics also occur [rx], which may contribute to the loss of muscle mass. Utilizing the Cochrane database [rx],
• S-Adenosylmethionine (SAMe) – SAMe, or AdoMet, is an obligatory intermediate in the conversion of methionine to cysteine in the hepatic transsulfuration pathway. SAMe is a precursor for syntheses of polyamines, choline, and glutathione (GSH), and it is the major methylating agent for a vast number of molecules via specific methyltransferases [rx].
• Vitamin E – Vitamin E deficiency has been well documented in ALD [rx]. Vitamin E has been used extensively with hepatoprotective effects in experimental models of liver injury such as that induced by carbon tetrachloride or ischemia. Vitamin E has multiple potential beneficial effects including membrane stabilization [rx], reduced NFκB activation and TNF production [rx], and inhibition of hepatic stellate cell activation and collagen production [rx]. Unfortunately, a major randomized study of vitamin E in ALD showed no benefit but may have used an inadequate dose (500 mg) [rx]. A smaller study with a higher dose (1,000 mg) of vitamin E in AH observed some normalization of serum hyaluronic acid levels but without significant changes in indices of liver damage [rx].
• Liver Transplant – A liver transplant may be the only treatment option in severe cases of ALD where the liver has stopped functioning, and there is no improvement even after the patient stops drinking. The consideration for a liver transplant is different, and it is only taken into account when the patient has developed complications of cirrhosis or if the body does not respond to other treatments including medications. However, ALD is one of the most common indications of a liver transplant.

Complications of Alcoholic Liver Disease

Following are significant complications of alcoholic liver disease:

• Variceal Hemorrhage – The patient presents with hematemesis or melena. Treatment options include endoscopic band ligation, sclerotherapy, and placement of transjugular intrahepatic portosystemic shunt placement (TIPS). TIPS increases the risk of hepatic encephalopathy.
• Ascites – This is the most common complication of alcoholic liver disease where there is an accumulation of fluid within the peritoneal cavity. The patient usually presents with abdominal swelling and pedal edema. Treatment options are sodium restriction, diuretics, paracentesis, and TIPS.
• Spontaneous Bacterial Peritonitis (SBP) – It is an infection of ascitic fluid without evidence of any other intraabdominal source (e.g., perforated viscus) of infection. The diagnosis is confirmed by positive ascitic fluid bacterial culture or ascitic fluid absolute neutrophil count of over 250/mm^3. Cefotaxime is a preferred antibiotic, but ciprofloxacin can be an option if the patient is not able to take cefotaxime.
• Hepatorenal syndrome – This is the development of renal failure due to advanced alcoholic liver disease after excluding other causes of renal failure. It characteristically demonstrates by a progressive rise in creatinine, low sodium excretion rate, oliguria, benign urinary sediment, and absence of proteinuria. Type 1 hepatorenal syndrome is a more severe type with at least a two-fold increase in creatinine in less than two weeks. It correlates with a high mortality rate. Type 2 is slower in onset and has a relatively better prognosis. Treatment for a critically ill patient includes norepinephrine and albumin. For noncritically ill patient treatment includes midodrine ( oral alpha agonist), octreotide, and albumin. The ultimate treatment is liver transplantation
• Hepatic hydrothorax – This is the presence of pleural effusion, and excludes other causes of pleural effusion. Treatment is diuretics, thoracentesis, and TIPS.
• Hepatopulmonary syndrome – It characteristically presents with elevated alveolar-arterial oxygen gradient on room air and evidence of intrapulmonary vascular abnormalities. The patient typically presents with shortness of breath and hypoxia. There is no treatment option except liver transplantation.
• Hepatic encephalopathy – It characterized by reversible neuropsychiatric abnormalities. Treatment includes lactulose, rifaximin, and correction of precipitating factors like infection, GI bleeding, etc.
• Other rare complications – are cirrhotic cardiomyopathy, hepatocellular carcinoma, portal gastropathy, portopulmonary hypertension, and portal vein thrombosis.
• Screening for hepatocellular carcinoma – with six-monthly ultrasonography and screening for esophageal varices in those with alcoholic cirrhosis
• Treatment of co-existent liver diseases such as Hepatitis B and C viral infections
• Chronic alcoholics are at increased risk of hepatotoxicity from acetaminophen, so dosing should not exceed more than 2 gm per day. A normal person can tolerate up to 4 gm of acetaminophen per day.

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