Fatty Liver corresponds to the presence of macrovesicular changes without inflammation (steatosis) and lobular inflammation in the absence of significant alcohol use. It can be divided into two subgroups: NAFL (Non-Alcoholic Fatty Liver) or simply Steatosis and NASH (Non-Alcoholic Steatohepatitis). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning), Mallory hyaline, and mixed lymphocytic and neutrophilic inflammatory infiltrate in the perivenular area with or without fibrosis.[rx] It is important to note that NAFL is a spectrum, with NAFL being the mildest form and NASH and cirrhosis being at the other end of the spectrum. NAFL (Non-Alcoholic Fatty Liver) or simply Steatosis and NASH (Non-Alcoholic Steatohepatitis) could only be distinguished with histology and liver biopsy.[rx].
NAFLD is commonly associated with Metabolic Syndrome, obesity, diabetes, and hyperlipidemia. Nearly 80% of patients with Metabolic Syndrome have NAFLD.[rx][rx][rx]
Etiological Causes of Fatty Liver
Fat accumulates in the liver for several reasons. Most commonly, it involves increased delivery of free fatty acids (FFAs) to the liver, increased synthesis of fatty acids in the liver, decreased oxidation of FFA, or decreased synthesis or secretion of very-low-density lipoprotein (VLDL).[rx][rx] Oxidative stress in the hepatocytes can activate stellate cells and lead to the production of collagen and inflammation.
Other factors that may contribute to the fatty liver include:
The use of medications (e.g., tamoxifen, amiodarone, methotrexate)
Metabolic abnormalities (e.g., glycogen storage disorders, homocystinuria)
Nutritional status (e.g., total parenteral nutrition, severe malnutrition, overnutrition, or a starvation diet)
Other health issues like Wilson disease and celiac sprue.
- Acquired metabolic disorders
- Diabetes mellitus
- Kwashiorkor and marasmus
- Cytotoxic and cytostatic drugs
- Highly active antiretroviral therapy
- Rare earths of low atomic number
- Thallium compounds
- Uranium compoundsInborn errors of metabolism
- Familial hepatosteatosis
- GalactosemiaGlycogen storage disease
- Hereditary fructose intolerance
- Systemic carnitine deficiency
- TyrosinemiaWeber-Christian syndrome
- Wilson disease
- Surgical procedures
- Biliopancreatic diversion
- Extensive small bowel resection
- Gastric bypassJejunoileal bypass
- Miscellaneous conditions
- Industrial exposure to petrochemicals
- Inflammatory bowel disease
- Partial lipodystrophy
- Jejunal diverticulosis with bacterial overgrowth
- Severe anemiaTotal parenteral nutrition
- Causes of nonalcoholic fatty liver disease[rx]
Causes of Fatty Liver
Fatty liver (FL) is commonly associated with metabolic syndrome (diabetes, hypertension, obesity, and dyslipidemia), but can also be due to any one of many causes:[rx][rx]
- Metabolic – abetalipoproteinemia, glycogen storage diseases, Weber–Christian disease, acute fatty liver of pregnancy, lipodystrophy
- Nutritional – obesity, malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunoileal bypass, gastric bypass, jejunal diverticulosis with bacterial overgrowth
- Drugs and toxins – amiodarone, methotrexate, diltiazem, expired tetracycline, highly active antiretroviral therapy, glucocorticoids, tamoxifen, environmental hepatotoxins (e.g., phosphorus, mushroom poisoning)
- Alcohol – Alcoholism is one of the causes of fatty liver due to the production of toxic metabolites like aldehydes during the metabolism of alcohol in the liver. This phenomenon most commonly occurs with chronic alcoholism.
- Other – celiac disease,[rx] inflammatory bowel disease, HIV, hepatitis C (especially genotype 3), and alpha 1-antitrypsin deficiency[rx]
- Personal and family history of diabetes, hypertension, and CVD
- Alcohol use: < 20 g/d (women), < 30 g/d (man)
- Waist circumference, BMI, changes in body weight
- Hepatitis B/C infection
- Liver enzymes
- History of steatosis-associated drug use
- Fast blood glucose, hemoglobin A1c
- Serum total and HDL-cholesterol, triacylglycerol, uric acid
- Undertaken due to clinical suspicion
- Hemochromatosis testing: Ferritin and transferrin saturation
- Celiac disease: IgA and tissue transglutaminase
- Thyroid disease: TSH level (T3/T4)
- Polycystic ovarian syndrome
- Wilson’s disease: Ceruloplasmin
- Autoimmune disease: ANA, AMA, SMA
- Alpha-1 antitrypsin deficiency: Alpha-1-antitrypsin level
Symptoms of Fatty Liver
Nonalcoholic fatty liver disease usually causes no signs and symptoms. When it does, they may include:
- Enlarged liver
- Pain in the upper right abdomen
- a poor appetite
- weight loss
- abdominal pain
- Swollen belly
- Enlarged blood vessels underneath your skin
- Larger-than-normal breasts in men
- Red palms
- Skin and eyes that appear yellowish, due to a condition called jaundice
- physical weakness
- abdominal pain
- an enlarging, fluid-filled abdomen
- jaundice of the skin and eyes
- abnormal bleeding
Possible signs and symptoms of nonalcoholic steatohepatitis and cirrhosis (advanced scarring) include:
- Abdominal swelling (ascites)
- Enlarged blood vessels just beneath the skin’s surface
- Enlarged breasts in men
- Enlarged spleen
- Red palms
- Yellowing of the skin and eyes (jaundice)
Diagnosis of Fatty Liver
Tests done to pinpoint the diagnosis and determine disease severity include:
- Complete blood count
- Liver enzyme and liver function tests
- Tests for chronic viral hepatitis (hepatitis A, hepatitis C and others)
- Celiac disease screening test
- Fasting blood sugar
- Hemoglobin A1C, which shows how stable your blood sugar is
- Lipid profile, which measures blood fats, such as cholesterol and triglycerides
Imaging procedures used to diagnose nonalcoholic fatty liver disease include:
- Plain ultrasound – which is often the initial test when liver disease is suspected.
- Computerized tomography (CT) scanning – of the abdomen. These techniques lack the ability to distinguish nonalcoholic steatohepatitis from nonalcoholic fatty liver disease but still may be used.
- magnetic resonance imaging (MRI)- of the abdomen. These techniques lack the ability to distinguish nonalcoholic steatohepatitis from nonalcoholic fatty liver disease but still may be used.
- Transient elastography – an enhanced form of ultrasound that measures the stiffness of your liver. Liver stiffness indicates fibrosis or scarring.
- Magnetic resonance elastography – which combines magnetic resonance imaging with patterns formed by sound waves bouncing off the liver to create a visual map showing gradients of stiffness throughout the liver reflecting fibrosis or scarring.
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|Mild (Grade 1)||Stage 1|
|Steatosis (mostly macrovesicular)||Zone 3 perisinusoidal/pericellular fibrosis (focal or extensive)|
|Involves up to 66% of biopsy|
|Occasional ballooned zone 3 hepatocytes||Stage 2|
|Scattered rare intra-acinar neutrophils with/without associated lymphocytes||Zone 3 perisinusoidal/pericellular fibrosis with associated focal or extensive periportal fibrosis|
|No/mild portal chronic inflammation|
|Moderate (Grade 2)|
|Ballooning hepatocytes-zone 3|
|Intra-acinar neutrophils-may be associated with zone 3 pericellular fibrosis||Stage 3|
|Portal and intra-acinar chronic inflammation||Zone 3 perisinusoidal/pericellular fibrosis and portal fibrosis with associated focal or extensive bridging fibrosis|
|Severe (Grade 3)|
|Intra-acinar inflammation with scattered neutrophils||Stage 4|
|Neutrophils associated with ballooned hepatocytes with/without chronic inflammation||Cirrhosis|
|Chronic portal inflammation-mild or moderate|
Treatment of Fatty Liver
- Avoiding alcohol. If you have alcoholic liver disease, then giving up alcohol is the most important thing you can do. Continuing to drink may result in you getting cirrhosis or alcoholic hepatitis. Giving up alcohol is also good for people with NAFLD.
- Losing weight. This is not easy for many people with fatty liver disease, so having a well-designed management plan designed by a doctor or dietitian can be beneficial. Gradual weight loss is the key, as sudden, severe weight loss can actually make the condition worse. Weight loss surgery may be recommended for some people.
- Exercising. Even if this does not directly result in weight loss, it is very worthwhile as exercise has been shown to reduce insulin resistance, a key factor in fatty liver disease. Both aerobic exercise and resistance training, such as low impact weight training, will help.
- Controlling your blood sugar levels.
- Reducing or avoiding soft drinks and juices and processed foods rich in sugar.
- Treating high cholesterol. Your doctor may suggest medicines to lower your cholesterol levels, in addition to dietary and lifestyle changes.
- Avoiding medicines that may affect your liver, such as some steroids. Do not take medicines that have not been prescribed by your doctor.
- Quit smoking. You will also be advised to quit smoking, to reduce your risk of heart disease.
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|– Diet with or without exercise|
|– Surgical treatment of obesity|
|Insulin resistance||Insulin sensitizing agents|
|– Thiazolidinediones (TZDs)|
|Dyslipidemia||Lipid lowering agents|
|– Omega-3 fatty acids|
|– Vitamin E|
|– Other vitamins|
|Pro-inflammatory cytokines||Anti-tumor necrosis factor agents|
|– Ursodeoxycholic acid (UDCA)|
|– ACE inhibitors/ARBs|
|– Incretin analogs|
ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers
Pharmacologic Treatment of NASH
Several drug therapies have been tried in both research and clinical settings, yet no agent has been approved by the Food and Drug Administration for the treatment of NAFLD[rx].
- Vitamin E, an inexpensive potent antioxidant, has been examined as a treatment agent for NAFLD in many adult and pediatric studies, with varying results. In all studies, vitamin E was well tolerated, and most studies showed modest improvements in the ultrasonographic appearance of the liver, serum aminotransferase levels and histologic findings[rx,rx,rx].
- In one published series of 11 pediatric patients with NASH who received vitamin E (d-α-tocopherol), 400 to 1200 IU, ALT improved [rx–rx].
- Few small trials assessed the usefulness of lipid-lowering and cytoprotective drugs for NAFLD treatment, with varying results. In one controlled trial, gemfibrozil improved liver chemistry in 74% of NAFLD patients in the treatment group, compared with 30% of untreated control subjects with no available histologic data. So, in general, lipid-lowering agents are not used for NASH treatment[rx].
- The association between hyperinsulinemic insulin resistance and NAFLD provides a logical target for treatment. Two classes of drugs have been shown to correct insulin resistance: biguanides (e.g., metformin) and thiazolidinediones.
- Metformin, a biguanide that reduces hyperinsulinemia and improves hepatic insulin sensitivity, reduces hepatomegaly and hepatic steatosis in ob/ob mice[rx], but results in human studies have been less impressive[rx,rx] as in human studies, although ALT improved and liver size decreased, metformin was not consistently found to improve liver histology[rx,rx].
- These drugs modulate tissue insulin sensitivity through the peroxisome proliferator-activated receptor (PPAR)-γ signaling and improve blood glucose control. Rosiglitazone and pioglitazone are the agents widely studied in this class of drugs for the management of T2DM.
- Following the controversy about increased cardiovascular events, rosiglitazone use has been much lower in recent years, with pioglitazone being the agent widely used currently. Pioglitazone has been shown to improve the hepatic insulin sensitivity and fatty acid oxidation and to inhibit hepatic lipogenesis.[rx]
- There is moderate quality evidence to suggest the benefits of pioglitazone in the improvement of biochemical and histological parameters of NAFLD, although the drug use may be associated with weight gain.[rx],[rx] In combination with intense lifestyle modification, this drug should be considered in patients with NASH.
- Oxidative stress plays a major role in the pathogenesis of NAFLD and several investigators studied the effects of antioxidants extensively.[rx]–[rx] Vitamin E is the most studied antioxidant in this group.
- Supplementation of this was associated with significant improvement in all histological parameters, such as steatosis, hepatocyte ballooning, lobular inflammation, and fibrosis, as compared to placebo.[rx] Vitamin E is used in the dose of 800 International Units daily for patients with NASH, especially in non-diabetic cases.[rx],[rx]
- Although multiple agents such as N-acetylcysteine, betaine, probucol, viusid, and silibinin (milk thistle) have been used in different trials, the use of these agents is not recommended in current clinical practice because of conflicting/insufficient evidence on the benefits.[rx]
- Although metformin use was associated with significant improvements in IR and liver transaminases (AST and ALT), the drug failed to show improvement in the histological parameters, such as steatosis, inflammation, hepatocellular ballooning and fibrosis.[rx]
- However, because of the antidiabetic efficacy, metformin should be considered for patients with T2DM or even prediabetic states and NAFLD. Metformin is found to be safe, even in patients with cirrhosis, and may protect against the development of HCC in cases with T2DM and chronic liver diseases.[rx]
- Ursodeoxycholate (UDCA) is a hydrophilic bile acid that is associated with hepatoprotective properties. In one study, UDCA produced improvement in liver enzymes and a decrease in hepatic steatosis. The long-term benefits of UDCA and the optimal dose of UDCA remain to be established[rx].
- Taurine is believed to function as a lipotropic factor and to improve the mobilization of hepatic fat. In another single uncontrolled series, 10 children treated with taurine supplements orally had a radiologic resolution of their fatty liver[rx].
- Betaine is a hepatoprotective factor, and liver histology and aminotransferase activity were improved in ten NAFLD subjects who received betaine for one year[rx,rx].
- In a recent randomized placebo-control study, 55 NASH patients received betaine (20 g daily). Patients randomized to betaine had a decrease in steatosis grade without a significant change in intragroup or intergroup differences in the NAS or fibrosis stage.
- Moreover, there was no significant change in adiponectin, insulin, glucose, proinflammatory cytokines, or oxidant stress in NASH patients receiving betaine therapy[rx].
- Pentoxifylline antagonizes TNF-α and is orally available for long-term use. In two small pilot studies, ALT improved after several months of treatment at a dose of 400 mg three times a day. In addition, although the drug was well tolerated in one study, 9 of 20 subjects in the other study dropped out because of side effects, especially nausea[rx,rx].
- Angiotensin II has been implicated in hepatic stellate cell activation and matrix production[rx]. In a small pilot study of an angiotensin receptor blocker, losartan, an improvement in ALT was noted[rx].
Drugs for weight loss
- Medications that help weight loss may potentially alter the pathogenic mechanisms of NAFLD and may be useful in selected patients. Most of these medications are associated with only modest weight loss benefit and several of them have been withdrawn from the market owing to undesirable side effects.
- This medication inhibits pancreatic lipase, resulting in fat malabsorption and weight loss as a consequence. Although two previous RCTs showed some beneficial effects of orlistat in patients with NASH, it is not clear if the benefit was related to weight loss conferred by the drug or direct effect.[rx–rx] Therefore, the drug use should be selected for individual patients as per the clinician’s discretion and situation.
- This is an appetite suppressant associated with about 4% weight loss in 12 months when combined with lifestyle changes.[rx] Pooled data from three lorcaserin RCTs showed that there was a modest reduction in ALT levels and improvement of cardiovascular outcomes in treated patients with NAFLD compared to placebo.[rx]
- This drug combination is associated with a weight loss of approximately 5%. Modest reductions in hepatic aminotransferase levels were observed in patients who lost > 10% weight in 12 months with a higher dose of the combination.[rx]
- This combination is also associated with significant weight loss benefit and may be associated with the improvement of NAFLD.[rx]
- High-dose liraglutide treatment (3 mg daily) has been approved by the United States’ Food and Drug Administration and the European Medicine Agency recently for primary management of obesity in patients without diabetes.
- About 8.5% weight loss has been observed in the treated patients compared to placebo in a major clinical trial, although the data on NAFLD was not available in this study.[rx] However, another recent phase 2 clinical trial reported significant improvement of liver histology when 1.8 mg liraglutide was administered to patients.[rx] Therefore, high-dose liraglutide treatment also may be associated with the same benefit.
Other novel agents
- Pentoxyphylline is a competitive nonselective phosphodiesterase inhibitor which raises cyclic adenosine monophosphate and inhibits tumour necrosis factor-α. Both animal studies and clinical trials in humans showed the beneficial effects of this novel agent.[rx,rx,rx]
- Although prebiotics and probiotics have been claimed to be useful in the treatment and prevention of patients with obesity and NAFLD, inadequate supporting data from high-quality clinical studies is against the recommendation of the use of these medications in normal clinical practice.[rx]
Glucagon-like Peptide-1 (GLP-1) Analogs
- GLP-1 analogs are stabilized (long-acting) agonists that bind receptors for the endogenous, intestinally-secreted hormone, GLP-1. Three members of this drug class are approved in the US, including exenatide, liraglutide, and albiglutide.
- They improve blood glucose control by enhancing glucose-dependent insulin secretion, slowing gastric emptying, suppressing postprandial glucagon production, and decreasing food intake through enhanced satiety. They are administered by subcutaneous injection (from twice daily to once weekly for different preparations), and they most often are used as second-line agents in conjunction with other glucose-lowering drugs or insulin.
- A recent small study from Japan showed improved steatosis and NASH histology (lower NAS score) following liraglutide treatment in overweight or obese subjects with prediabetes (rx). This was associated with improved glucose tolerance and a small decrease in BMI. While these initial data are intriguing, further studies will be needed to establish whether or not liraglutide or other GLP-1 analogs can be useful in preventing or treating NAFLD.
Dipeptidyl peptidase-4 (DPP-4) inhibitors
- DPP-4 inhibitors, currently sitagliptin, saxagliptin, linagliptin, and alogliptin in the US, influence glucose homeostasis by blocking the deactivation of endogenous GLP-1 and a second incretin hormone, glucose-dependent insulinotropic peptide (GIP).
- Some of the effects of DPP-4 inhibitors may overlap with those of administered GLP-1 analogues (as noted above), but these drugs likely have additional actions by increasing levels of hormones other than GLP-1. DPP-4 inhibitors have the advantage of being taken orally.
- Several clinical studies with sitagliptin in subjects with T2DM and NASH have shown decreases in alanine aminotransferase levels ([rx–rx] and, in two studies, improved liver histology [rx,rx].
- There are two main groups of incretin-related drugs extensively studied for use in NAFLD, viz., GLP-1 analogs (e.g., exenatide, liraglutide, lixisenatide, dulaglutide, and semaglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, vildagliptin, alogliptin and linagliptin).
- Both classes of drugs augment the meal-related insulin secretion from the pancreas, along with extra-pancreatic effects on multiple organs that make them very useful for the management of T2DM.[rx] Use of GLP-1 analogs are associated with weight loss, and DPP-4 inhibitors are weight neutral.
- incretin-based therapy is very commonly used in overweight/obese T2DM patients, many of whom suffer from NAFLD as well. Remarkable benefits of both the conditions make this class of agents unique in managing the cases.[rx]
- Bariatric surgery is the primary surgical intervention for NAFLD in patients with a BMI more than 40 kg/m2 or of 35 kg/m2 with comorbidities[rx]. Current bariatric surgical techniques include vertical banded gastroplasty, adjustable gastric banding, Roux-en-Y gastric bypass, biliopancreatic bypass, and biliopancreatic diversion with duodenal switch. Based on a recent meta-analysis, bariatric surgery is associated with significant histologic improvements in steatosis, steatohepatitis, and fibrosis, with more than 50% of patients experiencing complete resolution of their fatty liver disease after surgery. Although these results are compelling, these observational studies showed no relationship between histologic improvement and the amount of weight loss[rx].
Risk For Fatty Liver Disease
Researchers do not know the cause of nonalcoholic fatty liver (NAFLD). They do know that it is more common in people who
- Have type 2 diabetes and prediabetes
- Have obesity
- Are middle aged or older (although children can also get it)
- Are Hispanic, followed by non-Hispanic whites. It is less common in African Americans.
- Have high levels of fats in the blood, such as cholesterol and triglycerides
- Have high blood pressure
- Take certain drugs, such as corticosteroids and some cancer drugs
- Have certain metabolic disorders, including metabolic syndrome
- Have rapid weight loss
- Have certain infections, such as hepatitis C
- Have been exposed to some toxins
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