Sections
• Patient Education
• Presentation
• Predictive Measures
• Epidemiology
• Prognosis
• Laboratory Studies
• Ultrasonography, CT Scanning, and MRI
• Show All
• AASLD/ACG/AGA Guidelines for Workup of NAFLD
• Treatment
• Questions & Answers
fats in the
• Liver Biopsy and Histopathologic Examination
the accumulation of
triglycerides and other
between the processes
Overview
Overview
Fatty liver is the liver depends on the balance liver cell death liver cells. The amount of fatty acid in be accompanied by hepatic inflammation and acid beta-oxidationof delivery and removal. In some patients, fatty liver may include the following:• Decreased mitochondrial fatty the liver(steatohepatitis). Potential pathophysiologic mechanisms for fatty liver enhanced delivery of
fatty acids to of cause and
• Increased endogenous fatty acid synthesis or as very low-density lipoprotein (VLDL)No single pathway pathways in patients
• Deficient incorporation or export of triglycerides higher levels of
activation of Hedgehog nonalcoholic fatty liver effect has been found. However, some studies show disease. [] Tripodi et al reported that in increase in factor with the most advanced fatty liver to metabolic cirrhosis, which may be caused by an could play a disease (NAFLD), a procoagulant imbalance progresses from steatosis C. [] The investigators speculated that this imbalance with NAFLD.VIII and a reduction of protein disease and liver fibrosis, conditions commonly associated into the following role in the risk for cardiovascular alcoholic liver disease (ALD) can be divided • Alcohol-related cirrhosis
Pathologic changes observed in patients with (simple steatosis)• Alcoholic hepatitisconsumption. Fatty liver develops three groups:
• Alcoholic fatty liver and reversible consequence
of excessive alcohol
day. Many mechanisms of
Alcoholic fatty liver is an early than 60 g of alcohol per an increase in in every individual who consumes more of glycerol 3-phosphate (3-GP) after ethanol ingestion are related to form (NADH) in the liver. A higher concentration ethanol-induced fatty liver have been proposed. Increased hepatic levels of nicotinamide adenine dinucleotide (NAD+) to the reduced free fatty acids the ratio of the oxidized form fatty acids.An increase in through direct stimulation of 3-GP results in enhanced esterification of pathogenesis. Large amounts of
alcohol enhance lipolysis the release of has also been incriminated in the fatty acids in the liver and decreased energy stores of the adrenal-pituitary axis. In addition, chronic ethanol ingestion inhibits oxidation of mechanisms favor steatosis. Centrilobular localization of steatosis results from shift in the VLDL into the blood. All of these shift in lipid metabolism, along with a central zone.caused by relative hypoxia and a preferential oxidation of alcohol in the some useful insights, including the role redox reaction as a result of pathogenesis of alcoholic steatosis have provided consumption, contributes to the
Advances in the understanding of the of hepatic fatty acid metabolism. Its blockade, in animal models, along with ethanol effect of saturated of peroxisome proliferator-activated receptor alpha, which is crucial for the regulation by adipocytes, has been implicated in the protective The role of development of alcoholic fatty liver. In addition, induction of adiponectin, a hormone secreted fatty liver in mice.injury in mice. Hepatocyte death by fat against the development of alcoholic thought to be essential for ethanol-induced fatty liver
and mice after the early growth response-1 (EGr-1) transcription factor is and has been demonstrated in rats and that are apoptosis occurs in alcoholic fatty liver proteins that regulate apoptosis and necrosis mainly produced by ethanol feeding. This may be related to mitochondrial fatty liver models.Serum leptin, a cytokine-type peptide hormone decreased leptin action, whether due to shown to be induced in mouse the pathogenesis of
steatosis. Steatosis occurs with be independently correlated adipocytes, may play an important role in alcoholic liver disease, the serum leptin level appears to studies support the leptin deficiency or resistance. In patients with Data from animal studies and clinical liver, as well as with the grade of steatosis.
factor alpha (TNF-alpha) in the early stages of fatty fatty liver disease role of proinflammatory cytokine tumor necrosis The condition most commonly associated with (eg, amiodarone, tamoxifen, methotrexate), alcohol, metabolic abnormalities (eg, galactosemia, glycogen storage diseases, homocystinuria, and tyrosinemia), nutritional status (eg, overnutrition, severe malnutrition, total parenteral nutrition in alcoholic steatohepatitis.
Next:
Etiology
II diabetes, obesity, and hypertriglyceridemia.Other factors, such as drugs of lean families is metabolic syndrome. This includes conditions such as type Wilson disease) may contribute to
fatty liver disease. There are reports increase the risk [TPN], or starvation diet), or other health problems (eg, celiac sprue and birth weights appear to not only severe disease. [] Male sex may with nonalcoholic steatohepatitis (NASH). Low and high also raise the risk for more may influence the for development of pediatric NAFLD but controversial. []Several risk factors Next:also be a risk factor, but this remains (ALD), including the following:
Previousor may be development of advanced alcoholic liver disease population. Steatohepatitis may be
related to alcohol-induced hepatic damage
depend on alcohol, with several million
United States statistics
Steatosis affects approximately 25%-35% of the general in the United States abuse or the long term. []unrelated to alcohol (ie, nonalcoholic steatohepatitis [NASH]). Approximately 17.6 million people evolve into problems with alcohol over drinkers develop clinically more who binge drink that may users, [, ] but only about 10%-20% of chronic heavy disease (NAFLD) is found in
Fatty liver develops in 90%-100% of heavy alcohol detected in 1.2%-9% of patients undergoing routine liver biopsy. Nonalcoholic fatty liver NASH. []important alcoholic fatty liver disease (ALD) (eg, alcoholic hepatitis, cirrhosis). [] NASH has been 50% of patients undergoing bariatric surgery have alcohol differently as over 80% of patients who are obese, and more than groups. With respect to alcoholic steatosis, the liver handles thought to be
Age-related demographics
Fatty liver occurs in all age because of increased organ susceptibility. These phenomena are of the smooth the body ages, and alcohol toxicity increases with age developing with age, as well as to decreased function most common liver related to a mitochondrial transport defect oxidation.NAFLD is the indicate that pediatric endoplasmic reticulum and metabolism of CYP2E1-dependent microsomal ethanol States, including about 8% of lean teens. [] However, findings from the
Project Viva study of development of disease among adolescents in the United age 8 years increases the risk most common cause overweight or obesity as early as more severe grading of fibrosis. NASH is the and hepatitis C). [] It is now NAFLD. [, ] Older age often is predictive of in the United States (followed by ALD after pediatric or of chronic liver disease in adults elevations of transaminases. NASH has recurred within 6 months lower doses of probably the leading reason for mild severe ALD more quickly and at sex-dependent differences in adult liver transplantation. [, , ]
Sex-related demographics
Women develop more of females may be related to female patients was alcohol than men do. The increased susceptibility metabolism of alcohol. In initial studies of NAFLD, the percentage of Findings from a the hepatic metabolism of alcohol, cytokine production, and the gastric 75%; however, in subsequent studies, the percentage fell to roughly 50%.and cirrhosis vary reported to be as high as and prevalence of chronic liver disease
Race-related demographics
disease, followed by white 2016 study demonstrated that the causes the most affected by chronic liver of chronic liver widely among different racial/ethnic groups. [] Japanese Americans (6.9%) and Latinos (6.7%) appear to be Native Hawaiians (3.9%). NAFLD was the most common etiology by ethnicity were persons (4.1%) as well as black persons and the groups; however, the most common causes of cirrhosis Very little data disease and of cirrhosis among all persons; and hepatitis C in black persons. []suggested overall differences. A study of NAFLD in Japanese Americans, Native Hawaiians, and Latinos; ALD in white the incidence of ALD; however, some studies have
the most likely are available on racial differences in drinking patterns among different races; white individuals were heavy drinking. [] Other studies have 42,862 US adults showed differences in volume of intake and frequency of been found across to drink, but black individuals had the highest among black persons.Fatty liver has that most of shown a higher rate of cirrhosis white persons, and it is
in this population white patients unless all races, but NAFLD is most common in have higher rates of NASH than a higher risk the research has been done. In general, Hispanics do not appear to put white individuals at disease in the diabetes is also present. [] Mutations for hemochromatosis A small study evaluating fatty liver simple lifestyle habits. [] However, obesity, when present, was a significant for more advanced fibrosis. []
the nonobese and its recovery with Next:Indian population found its association with in Koreans. []Previousbelieved to be risk factor for NASH in Indians, as well as loss, cessation of alcohol
use, or both. It was once
to liver fibrosis
Prognosis
Steatosis may be reversible with weight progressed to chronic liver disease; however, steatohepatitis may progress Simple alcoholic steatosis a benign condition that only rarely liver-related morbidity and mortality.more advanced forms and cirrhosis and may result in within 2-4 weeks. Continued alcohol consumption may result in
with a favorable is rarely fatal. With complete abstinence, histologic changes generally return to normal usually is considered a benign lesion that may indicate of liver disease, either alcoholic hepatitis or cirrhosis. Although alcoholic steatosis have been described in the literature For example, in a study prognosis once alcohol consumption is discontinued, several prognostic factors patients who continue to drink.of 10.5 years, 9 of the advancement to more severe lesions in with fatty liver for a mean
to use alcohol. [] Histologic predictors of from England that followed 88 patients of these 16 patients had continued macrovesicular/microvesicular fat and patients developed cirrhosis, and 7 developed fibrosis; all but 1 liver included the presence of mixed of the development progression at the time of fatty fatty liver are at high risk the index liver giant mitochondria.
Patients with alcoholic with the severity of steatosis in appear to be of cirrhosis and increased mortality associated association with alcoholic steatosis does not retrospective study noted biopsy. The presence of histologic cholestasis in risk of progression to cirrhosis. More recently, investigators of a prognosis in patients of prognostic significance in determining the carcinoma, alcoholic liver disease (ALD) confers a worse liver disease (NAFLD)-related cirrhosis. []that, despite a lower incidence of hepatocellular hepatitis C infection or nonalcoholic fatty increase in mortality with cirrhosis than those with chronic the Danish National Registry noted an after the censoring
A study from Denmark that used diagnosis of alcoholic fatty liver; this increase remained studies of patients among patients with a hospital discharge cirrhosis. []Long-term natural history 3-year period without of patients with a diagnosis of have shown that
30% progress, 30% remain stable, and 30% improve over a nonalcoholic steatohepatitis (NASH). []with NAFLD who undergo repeat biopsies independent risk factor for progression of patients than in pharmacologic intervention. [] Abnormal glucose tolerance testing is an County, Minnesota, revealed that over the 10-year study period, mortality was 10% higher in NAFLD the third leading
A natural history study from Olmsted top two causes of death. Liver-related disease was cause of death control subjects. [] Malignancy and heart disease were the but only the 13th most common in 500 patients cause of death (13%) for NAFLD patients by Bhala et al evaluating mortality of liver-related disease; however, long-term mortality for with chronic hepatitis
In a study C were more likely to die cardiovascular causes of NASH was equivalent C or NASH, patients with hepatitis hepatitis C, probably because of the increase in is present in death found in to that for Fibrosis or cirrhosis of the liver cryptogenic cirrhosis may 15%-50% of patients with the NASH patients. []
fibrosis develop cirrhosis after 10 years. Many cases of obesity, type II diabetes, or hyperlipidemia.represent so-called burnt-out NASH because NASH. Approximately 30% of patients with of such cases are associated with hepatic failure. Some patients with Some patients with a high percentage present dramatically with rapid evolution of may result in
inborn errors of drug-induced fatty liver to cirrhosis.Continued alcohol consumption from Denmark, using a population-based National Registry, investigators noted an a more advanced metabolism (eg, tyrosinemia) may rapidly progress disease, either alcoholic hepatitis
Complications
or cirrhosis. In a study of alcoholic fatty increased mortality and form of liver risk, particularly liver cancer, among patients discharged with a diagnosis to cirrhosis, accompanied with complications liver. []an increased cancer nonalcoholic fatty liver disease (NAFLD), steatohepatitis may progress more than one that include variceal
In patients with progression appears to be worse if to predict worse liver disease (eg, alcoholic liver disease bleeding, ascites, encephalopathy, and liver failure. The rate of hepatitis) is present. Uncontrolled diabetes and hypertriglyceridemia also appear as with other fibrosis. [, , , ] The rate of [ALD] or chronic viral carcinoma appears to be the same carcinoma in patients forms of liver formation of hepatocellular to increase the risk for hepatocellular risk factor for clinical situations (ie, life expectancy >20 years).whose livers are disease, [] although NAFLD appears to be a strong and independent Fatty liver was prediabetes in the not cirrhotic. [] NAFLD also appears PreviousNext:this is not once considered to
general adult population. []
benign condition, but it is
Patient Education
now clear that mainstays of therapy. Ideally, during every healthcare always the case. Thus, patient education on be an entirely portions is essential. Nutrition and lifestyle education are the organizations offer excellent provider encounter, the issues of dietary decisions and and reviewed. In addition, the American Diabetes Association and other an increased risk dietary and lifestyle food choices, food portions, and exercise, including weight-bearing exercise, should be emphasized Patients with heavy they are at be counseled on day) for longer than
advice.be counseled that fatty liver should progression to more for alcoholic liver 5 years should Patients with alcoholic and the likely from alcohol early the detrimental role
disease. []their liver problem to emphasize abstinence eliminate, the development of advanced liver disease alcohol plays in use. It is important histology, decreases portal hypertension, and decreases, but does not nature of alcoholism.and continuously so with continued alcohol its beneficial effects. Abstinence improves liver of the addictive Previouscirrhosis. Alcohol rehabilitation should as to optimize all patients, with an understanding address: 5000 Fishers Lane, Rockville, MD 20857; Phone: 877-SAMHSA-7 (877-726-4727) or 800-487-4889 (TTY)moderate or large Substance Abuse and be offered to Administration (SAMHSA): Headquarters and mailing ingestion of a
of the liver Next:Mental Health Services commonly after the
is asymptomatic. Severe fatty infiltration
A thorough clinical
History
amount of alcohol, even for a Fatty liver occurs time. Alcohol-induced steatosis usually to the hospital.of alcohol in can result in short period of in 15% of patients admitted determining the role reveal past alcohol-related problems. No specific test history, especially with regard symptoms of malaise, weakness, anorexia, nausea, and abdominal discomfort. Jaundice is present of alcohol consumption, is essential for
family members may medications, including over-the-counter medications and the etiology of to the amount results. History obtained from concurrent and recent The 2010 American is available to abnormal liver test review of all liver test results.(ALD) recommends the following alternative treatments, is valuable in rule out drug-related toxicity, but a good causes of abnormal alcoholic liver disease fatty liver or Association for the evaluating the possible Diseases (AASLD) practice guideline for
disease (NAFLD) are asymptomatic. However, if questioned, more than 50% of patients with patients with cirrhosis for diagnosis [] :Study of Liver nonalcoholic fatty liver disease, such as ascites, edema, and jaundice, may arise in examinations often reveal
nonalcoholic steatohepatitis (NASH) report persistent fatigue, malaise, or upper abdominal Most patients with Symptoms of liver life insurance physical liver disease.due to progressive
discomfort.blood donations or diagnosis of fatty noted on the elevated alanine aminotransferase NASH. Laboratory abnormalities during lead to the of any abnormalities steatosis proven on Alcoholic fatty liver (ALT) levels and ultimately in the absence 70% of persons with
Physical Examination
Hepatomegaly is also physical examination. Hepatomegaly is common may be present are hospitalized, occurring in over muscle wasting, cardiomyopathy, pancreatitis, or peripheral neuropathy, may be present.(eg, ascites, edema, spider angiomas, varices, gynecomastia, and menstrual disorders) may occur in biopsy. Portal hypertension is in patients who steatosis. Extrahepatic effects, such as skeletal of portal hypertension Previouscommon with nonalcoholic rare in alcoholic (NAFLD). Splenomegaly and stigmata
failure.conditions:patients with cirrhosis. Patients with drug-induced fatty liver fatty liver disease rapid fulminant liver includes the following • Alcohol excessNext:may present with is broad and
conditions:
NASH can be
Differential Diagnosis
Steatosis can be The differential diagnosis in the following • Nonalcoholic steatohepatitis (NASH) – A diagnosis of
valproic acid, tetracycline, antiviral agents such • Starvationobserved on histology (TPN)
(eg, disease caused by
• Reye syndrome
established only when • Total parenteral nutrition
• Drug-induced liver disease errors of metabolismfrom the American as zidovudine, amiodarone, perhexiline maleate, methotrexate, corticosteroids, or estrogens)
• Metabolic liver disease and other inborn 2018 practice guideline Gastroenterological Association (AGA) regarding the workup
PreviousNext:Recommendations from a
of Gastroenterology (ACG), and the American
Fasting insulin and
Association for the
AASLD/ACG/AGA Guidelines for Workup of NAFLD
Study of Liver Diseases (AASLD), the American College Next:lead to more of nonalcoholic fatty liver disease (NAFLD) are below [Previousintolerance and may to alcohol use, but this study glucose levels will
alert the clinician
to potential glucose
Laboratory Studies
glutamyl transpeptidase (GGT) may be related normal values.effective therapies.An increase in the levels of abuse alcohol have with alcoholic steatosis
lacks specificity and sensitivity, and as many as 70% of people who described five patients and marked cholestasis In rare cases, patients with alcoholic steatosis have severe cholestasis. Ballard et al showed severe steatosis
in and led who presented with jaundice, all of whose liver biopsy results and coagulopathy developed (ALD) conducted by the with little hepatic fibrosis. Hepatic failure characterized by progressive encephalopathy alcoholic liver disease alcoholic steatosis.to death in two patients. [] In a large cooperative study of 19% of patients with specificity (85%-91%). Serum carbohydrate-deficient transferrin (CDT) is a specific Department of Veterans Affairs (VA), histologic cholestasis was observed in only sensitivity (27%-52%) and a high g/day.Macrocytosis (increased mean cell volume) is common in patients with ALD, with a low intake exceeds 60
(NAFLD). Increased triglycerides are and sensitive test for alcoholism in patients whose alcohol fatty liver disease (ALP) level can be Hypertriglyceridemia, steatosis, and hemolysis (Zieve syndrome) may be associated with alcohol abuse. Hyperlipidemia may be present in nonalcoholic The alkaline phosphatase
three times normal.common in children and in patients with metabolic syndrome.than twice to one third of elevated in some patients with nonalcoholic
steatohepatitis (NASH). Usually, it is less found in about the indirect reacting Abnormal levels of aminotransferases (ie, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and bilirubin are an increase in
of serum AST hospitalized patients with alcohol-induced steatosis. In such patients, elevated bilirubin levels largely result from ALT measurements. The absolute values or ALT level fraction and may reflect alcohol-associated hemolysis. AST levels are usually higher than An elevated AST be elevated as and ALT are almost always less than 500 IU/L.liver; these levels may liver or NASH. In the absence may be the only abnormality in
patients with fatty patients with fatty 1 may occur much as 10-fold. However, AST and ALT levels may be normal in some of less than be obtained to of cirrhosis, an AST-to-ALT ratio greater than 2 suggests alcohol use, whereas a ratio hepatitis C should tests should be in patients with NASH.Viral serologies for from liver function occur in patients identify or exclude
viral infection. In addition, iron levels and total iron-binding capacity (TIBC) should be measured, and abnormal results levels, decreased transferrin saturation, or both may more severe disease. Evidence exists that evaluated as indicated.Elevations in serum ferritin or iron patients with NASH, these patients have in patients with
with NASH. Although iron overload occurs in a small proportion of the normal range hepatic fibrosis. [] An iron index a serum ferritin greater than 1.5 times the upper limit of (and thus, NASH) and with advanced phlebotomy. Hemochromatosis gene testing NAFLD is associated with a higher NAFLD activity score to evaluate for Autoimmune markers, such as antinuclear score may be ordered on a liver biopsy specimen iron has been thiazolidinedione.is recommended when the ferritin is significantly elevated. Simply eliminating dietary • Etiology]fatty liver.• Sections Fatty Liver• Overview• Differential DiagnosisAtorvastatin was studied
for 1 year with repeat biopsies and was shown to yield improvement with respect to ballooning degeneration and inflammation. The drug was combined with vitamin C 1 g and vitamin E 100 IU and
compared with placebo in a study lasting longer than 3 years. [] This study used computed tomography (CT) scan measurements to diagnose liver disease and demonstrated that the odds of developing fatty liver were 34% with treatment and 70% without treatment. []Gemfibrozil has resulted in biochemical improvement, but histologic data are lacking. Ezetimibe was studied in a Japanese
population in conjunction with lifestyle changes and yielded improved results on follow-up liver biopsy in 6 of 10 patients after only 6 months. []Vitamin E and ursodeoxycholic acid (ursodiol) have brought about improvements in specific populations. Data on the latter are conflicting in both adults and children: Some studies show biochemical and histologic improvement, whereas others studies show no difference from placebo.]Early studies reporting possible worsening of hepatic function after rapid weight loss have not been
substantiated. Thus, bariatric surgery may be a viable alternative in appropriate candidates.All patients with chronic liver disease should be tested for hepatitis A total antibodies and vaccinated if necessary. Physicians should also
day; women: >2 drinks per consider testing for hepatitis B surface antibody and vaccinating in the appropriate inflammation to predict fibrosis in patients with NAFLD as well as to predict the presence of NASH. [] The investigators noted that patients with NASH had elevated levels of mean platelet volume and neutrophil-lymphocyte ratio compared to those without NASH, as well as in patients with advanced fibrosis compared to those with early fibrosis. []PreviousNext:
Noninvasive studies such
as ultrasonography (US), computed tomography (CT) scanning, and magnetic resonance
Ultrasonography, CT Scanning, and MRI
imaging (MRI) are useful in helping to establish a diagnosis of steatosis, as well as in finding evidence for portal hypertension; these imaging tests are also helpful in ruling out biliary dilation (eg, choledocholithiasis) in patients with a cholestatic pattern of liver test result abnormalities.However, these imaging modalities can neither define
the cause of steatosis nor reliably distinguish between benign steatosis and steatohepatitis. Benign steatosis may be focal or diffuse, whereas steatohepatitis is usually diffuse.In patients with alcoholic steatosis, the liver appears
diffusely echogenic on US. In patients with nonalcoholic fatty liver disease (NAFLD), the liver is hyperechogenic or bright. Steatosis is detected only when substantial (≥ 30%) fatty change is present. Studies in patients who are about to undergo gastric bypass surgery indicate that US has a 93% predictive value for NAFLD, with an accuracy of 76%. Patients with steatosis on US have a higher incidence of coronary artery disease and should undergo cardiac evaluation if suspicious symptoms are present. []The mean CT (Hounsfield unit) count is lower
in the liver than in the spleen. CT scans may be used to monitor the course of the disease on successive scans. Focal fatty lesions may be identified by dual-energy CT scans that demonstrate increased attenuation with increasing energy.MRI may be useful for excluding
fatty infiltration. Phase-contrast imaging correlates with the quantitative assessment of fatty infiltration across the entire range of liver disease. Loss of intensity on T1-weighted images may be useful in identifying focal fat. More recently, investigators indicate that two-dimensional magnetic resonance elastography (MRE) can measure shear hepatic stiffness as a biomarker of fibrosis in children with NAFLD, but further investigation is needed to better refine, validate, and integrate MRE into clinical protocols. []PreviousNext:
The readily obtained
nonalcoholic fatty liver
Predictive Measures
disease (NAFLD) fibrosis score—consisting of age, hyperglycemia, body mass index (BMI), platelet count, albumin level, and ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT)—appears easy to use for this purpose and promising for helping to avoid excessive liver biopsies. []Another promising tool is the method
Kotronen et al developed for predicting NAFLD, which is based shown to improve antibody (ANA) and anti–smooth muscle antibody (ASMA), are often slightly elevated in NASH. Positive antibodies are associated with more severe fibrosis levels. In the appropriate clinical setting, serum protein electrophoresis (SPEP) and anti–liver-kidney antibody may lead to a diagnosis of autoimmune liver disease.Often, a clinical picture of obesity, hypertriglyceridemia, and elevated transaminases
is enough to allow the clinician to conclude that
a patient has
NASH. However, underlying alcohol or
other drug ingestion, as well as
smoldering autoimmune disease or hemochromatosis, must be ruled out. Referral to a hepatologist with or without liver biopsy may help in staging and prognosis.Serum beta-trophin level may have potential as a new marker
for noninvasive evaluation of NAFLD and liver fibrosis, according to a study by Cengiz et al. [] In their cohort of 69 patients
with NAFLD and
69 healthy control
Liver Biopsy and Histopathologic Examination
subjects, serum beta-trophin levels were lower in the NAFLD group; those with mild fibrosis had elevated serum beta-trophin levels compared to those with significant fibrosis. In multivariate and ROC (receiver operating characteristic) analyses, levels of serum beta-trophin was, respectively, an independent predictor of significant fibrosis and was statistically significant in identifying significant fibrosis. []Findings from the Multi-Ethnic Study of Atherosclerosis (MESA) appear to indicate
that circulating interleukin-6 (IL-6) is a biomarker
for coronary atherosclerosis in NAFLD. [] IL-6 had an independent association with
the prevalence and severity of subclinical
atherosclerosis.
In a separate study, Abdel-Razik et al alcohol use (men: >3 drinks per proposed mean platelet volume and the neutrophil-lymphocyte ratio as novel inexpensive and simple markers of would have in guiding therapeutic options. For patients who are unlikely to receive specific treatments or who have conditions that make a biopsy unsafe, the 2018 ALD guideline recommends including procedure risk in the biopsy decision. []A liver biopsy
and histopathologic examination are required to establish the diagnosis of nonalcoholic fatty liver disease (NAFLD). The diagnosis should be considered in all patients with unexplained elevations in serum aminotransferases (eg, with findings negative for viral markers or autoantibodies or with no history of alcohol use). It should also be considered in patients with NAFLD who are at increased risk of having steatohepatitis and/or advanced fibrosis. [] The Brunt classification is the standard used to report NAFLD and nonalcoholic steatohepatitis (NASH) biopsy specimens. []Histologically, fatty liver is
Histologic findings
characterized by fat accumulation, which is most prominent in the pericentral (centrilobular) zone. Macrovesicular steatosis is the rule; hepatocytes containing one or more large fat droplets displace the nucleus to an eccentric position. Occasional lipid release from rupture of distended hepatocytes may produce a mild localized inflammatory response (lipogranulomas) composed predominantly of macrophages and occasional lymphocytes.Although infiltration of
liver with inflammatory cells typically is not prominent in patients with steatosis alone, in some instances, fibrosis around terminal venules (ie, perivenular fibrosis) or hepatocytes (ie, pericellular fibrosis) has been noted. Early changes observed with the electron microscope include accumulation of membrane-bound fat droplets, proliferation of smooth endoplasmic reticulum, and gradual distortion of mitochondria. Microvesicular steatosis also is being recognized with increasing frequency.Alcoholic foamy degeneration
(microvesicular fatty change) was the term used by Uchida et al to describe a clinical syndrome in people with chronic alcoholism. [] The syndrome is characterized by jaundice and hyperlipidemia and is associated with striking microvesicular steatosis and abundant giant mitochondria observed on liver biopsy.Specific histologic findings
in NAFLD or NASH include the following:• Steatosis, which usually is
macrovesicular but may be microvesicular or mixed• Inflammatory infiltrates consisting
of mixed neutrophilic and mononuclear cells, usually without portal infiltrates (in contrast to hepatitis C)• Ballooning degeneration
• Fibrosis
The first three
findings are used to calculate the NAFLD activity score, which is determined on a scale of 0 to 8. The stage of disease is determined by the NAFLD activity score and the amount of fibrosis present.Previous
Next:
No definitive pharmacologic
Treatment & Management
therapy has been approved for treatment of nonalcoholic fatty liver disease (NAFLD). Management of NAFLD should include treating the associated obesity, hyperlipidemia, insulin resistance, and type 2 diabetes.Although alcohol-induced hyperhomocysteinemia (which has been
associated with endoplasmic reticulum stress leading on routinely available clinical and laboratory data. [] Analysis of 470 subjects in whom liver fat content was measured with proton magnetic resonance spectroscopy showed the following to be independent predictors of NAFLD [] :• Presence of metabolic
syndrome and type 2 diabetes• Fasting serum insulin• Fasting serum AST• AST-to-ALT ratioValidation of the score demonstrated an area under the receiver operating characteristic curve of 0.86. [] The optimal cut-off point of –0.640 predicted increased liver fat content with a sensitivity of 86% and a specificity of 71%.
Other noninvasive commercial tests for fibrosis (eg, FIBROSpect, FibroSURE, and FibroScan) have not yet been proved useful for NASH in Western populations.PreviousNext:Liver biopsy and histopathologic examination are important components of the diagnostic evaluation in patients with
suspected alcoholic liver disease (ALD). They are the most sensitive and specific means of evaluating the degree of liver cell injury and hepatic
fibrosis. Several reasons justify obtaining a liver biopsy in patients with ALD, including the following:• Confirming the diagnosis• Excluding other unsuspected causes of liver
disease• Assessing the extent of liver damage• Defining the prognosisIn making the decision on whether to perform a biopsy, it is important
to consider the strength of the clinical diagnosis and the role that the biopsy findings nonheavy alcohol consumption.• Pharmacologic treatments should
be limited to individuals with biopsy-proven NASH and fibrosis.• Vitamin E 800
IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH; it should therefore be considered as a first-line pharmacotherapy for this patient population, and the risks and benefits should be discussed with the patient prior to starting treatment.• Omega-3 fatty acids
may be considered for hypertriglyceridemia in patients with NAFLD, but it is premature to recommend them for the specific treatment of NAFLD or NASH.• Metformin is not
recommended as a specific treatment for liver disease in adults with NASH.• Pioglitazone may be
used to treat steatohepatitis in both patients with and without type 2 diabetes with biopsy-proven NASH, but the risks and benefits should be thoroughly discussed with the patient prior to initiation of treatment.• Glucagon-like peptide (GLP)-1 agonists have
been studied to treat liver disease in patients with NAFLD or NASH; however, it is still premature to consider these agents as treatment options at this time.• Foregut bariatric surgery
is not contraindicated in otherwise eligible obese individuals with NAFLD or NASH but without established cirrhosis; however, it is premature to consider foregut bariatric surgery as an established option to treat NASH specifically.• Ursodeoxycholic acid (UDCA) and obeticholic acid
(OCA) are not recommended to treat NASH or NAFLD.• Statins can be
used to treat dyslipidemia in patients with NAFLD and NASH, but they should not be used specifically to treat NASH, pending evidence from randomized controlled trials. Statins should be avoided in patients with decompensated cirrhosis.No specific dietary
Diet and weight loss
restrictions are needed in patients with simple alcoholic steatosis. Patients with alcoholic fatty liver may have deficiencies of vitamins, minerals, and trace elements. Adequate replacement of these deficiencies should be a part of management. Protein-calorie malnutrition is a common finding in patients with alcoholic liver disease (ALD) and is associated with the major complications observed with cirrhosis. Consequently, it is vital to recognize and understand the significance of malnutrition in these patients.A low-fat American Diabetes
Association (ADA) diet is recommended, and a weight loss goal of 1-2 pounds per week is suggested. Diets associated with improvement include those restricted in rapidly absorbed carbohydrates and those with a high protein-to-calorie ratio. Weight loss should be gradual, moderate, and controlled. []Mounting evidence indicates
that high-fructose diets (eg, sodas and preserved foods) are factors for developing fatty liver and that their elimination may reverse fatty liver. [, ] The mechanism appears to be related to depletion of adenosine triphosphate (ATP), as well as to apoptosis and up-regulation of lipid synthesis) and its correction by betaine have
been studied in animal models, no definite role of the use of betaine to treat alcoholic fatty liver in humans is available.Weight loss and control of comorbidities appear to slow the progress of NAFLD and may
reverse some of the steatosis and fibrosis. In a randomized trial, improvement on liver
Exercise
biopsy was seen after a 7% weight loss resulting from lifestyle changes (improved diet, exercise, and behavioral modification). [] No established treatment is available for nonalcoholic steatohepatitis (NASH).Although no proven medical therapy is available, a study by Foster et al found that atorvastatin 20 mg, combined with vitamins C and E, is effective in alcohol excess (>10 g/day) can be excludedreducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD after 4 years of
active therapy. []The 2018 practice guidelines from the American Association for the Study of Liver Diseases (AASLD) include the following recommendations regarding treatment of NAFLD [] :• Weight loss of 3%-5% of body weight generally reduces hepatic steatosis, but up to 10% weight loss may be needed to improve necroinflammation.• A combination of reduced calorie diet and moderate intensity exercise may aid in sustaining weight loss, along with aggressive modification of cardiovascular risk factors.• Patients with NAFLD
Pharmacologic therapy
should not consume heavy amounts of alcohol; data are insufficient to make recommendations with regard to lasting only as long as the medication is being delivered. [
A randomized placebo-controlled trial comparing pioglitazone plus diet with diet alone in 55 patients undergoing liver biopsy reported improvements in the transaminase levels and steatosis; however, the fibrosis score improved only within the pioglitazone group before, not after, the 6-month treatment. [] The posttreatment differences between the pioglitazone group and the placebo group were not statistically significant. Larger, longer studies are warranted.
In a study published in 2010, nearly 250 patients with NASH were divided into three groups as follows [] :
• Group 1, pioglitazone 30 mg/day
• Group 2, vitamin E 800 IU/day
• Group 3, placebo
After 96 weeks, each patient underwent a follow-up liver biopsy. Group 2 patients showed the most improvement on their liver biopsies. Both group 1 and group 2 patients showed improvements in liver lab test results and fatty liver inflammation numbers. However, group 1 patients gained the most weight and did not improve their liver scar readings. []
Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity. It is sold both as a single-ingredient product under the brand name Avandia and as combination products under the brand names Avandamet (rosiglitazone with metformin) and Avandaryl (rosiglitazone with glimepiride).
Rosiglitazone was studied for 48 weeks in 30 patients with NASH and was found to yield biochemical as well as histologic improvement. [] In a randomized, open-label trial, rosiglitazone plus metformin was compared with rosiglitazone plus losartan and with rosiglitazone alone after 48 weeks of therapy in 137 subjects with biopsy-proven NASH; the combination regimens yielded no greater benefit than rosiglitazone alone with respect to histopathology. []
The 2007 publication of a meta-analysis raised concerns among patients and healthcare professionals that rosiglitazone was potentially associated with an increased risk of myocardial infarction (MI) and heart-related deaths. [] A 2010 update of this meta-analysis concluded that the totality of the randomized clinical trials continued to demonstrate increased risk for MI (though not for cardiovascular or all-cause mortality) and that the available findings suggested an unfavorable benefit-to-risk ratio for rosiglitazone. []
As of November 18, 2011, the US Food and Drug Administration (FDA) requires that healthcare providers must enroll in the Avandia-Rosiglitazone Medicines Access Program if they wish to prescribe rosiglitazone medicines to outpatients or patients in long-term care facilities. (See Safety Alert on Avandia [last updated 11/4/2011]).
Patients currently taking rosiglitazone and benefiting from the drug may continue if they choose to do so. Rosiglitazone is available to new patients only if they are unable to achieve glucose control on other medications and are unable to take pioglitazone, the only other to increased uric
acid production from
excess fructose. []In mouse models of NASH, a high-fat diet combined with a high-fructose diet (equivalent to the typical American “fast food diet”) resulted in more liver damage than a high-fat diet alone. [] In a study of rats on a high-fructose diet, exercise (swimming 1 hour a day, 5 days a week) prevented the development of fatty liver disease. []NAFLD can be prevented in most patients by taking the following measures:Multiple human studies have shown that exercise added to diet appears to improve the results and increase insulin
sensitivity by increasing muscle mass. Exercise that includes both cardiovascular fitness and weight training should improve NASH. Cardiovascular fitness often results in weight loss. Weight training will increase the muscle mass and improve insulin sensitivity. Combining these two activities helps relieve
the underlying derangements of NASH.Even regular exercise that is not associated with weight loss has been shown to improve fatty liver disease. [, , ] An Australian study evaluating just 4 weeks of cycling exercise found that
Experimental therapy
despite no change
Bariatric surgery
in body weight, liver cholesterol levels improved. [] A California study involving more than 800 adults with fatty liver found that vigorous exercise was associated with less severe scar tissue in the
Long-term monitoring
liver. [] Most experts agree that walking for 20 minutes 5-7 days a week can stabilize liver disease.Thiazolidinediones have been shown to decrease inflammation in the liver in both humans and rats, with the effects All patients with
chronic liver disease are at risk for liver disease progression.Patients should be
educated to avoid alcohol and other hepatotoxic substances. If patients have a liver insult from another liver problem, they may have longer recovery times than patients without (<1%) for control subjects.fatty liver disease would.
Patients with fatty liver disease should be seen regularly by a primary care physician, who may be able to detect disease progression through physical examination findings (eg, spider telangiectasia, palmar erythema, or splenomegaly), laboratory findings (eg, decreasing platelets, elevated bilirubin, or decreasing albumin), patient complaints (eg, encephalopathy, ascites, or fatigue), or incidental imaging study findings (eg, cirrhotic liver, splenomegaly, varices, or ascites).
Patients who have NASH cirrhosis should be screened for gastroesophageal varices as well as hepatocellular carcinoma.
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References
• Akhtar S. Liver, biliary tract and pancreas. Solved Question Papers of Pathology and Genetics for BSc Nursing. New Delhi, India: Jaypee Brothers Medical Publishers; 2012.
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Contributor Information and Disclosures
Emily Tommolino, MD Chief Resident, Department of Internal Medicine, Providence Hospital
Emily Tommolino, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.
Michael H Piper, MD Clinical Assistant Professor, Department of Internal Medicine, Division of Gastroenterology, Wayne State University School of Medicine; Consulting Staff, Digestive Health Associates, PLC
Disclosure: Nothing to disclose.
Chief Editor
BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Dawn Sears, MD Associate Professor of Internal Medicine, Division of Gastroenterology and Hepatology, Scott and White Memorial Hospital
Dawn Sears, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology
Disclosure: Nothing to disclose.
Acknowledgements
Simmy Bank, MD Chair, Professor, Department of Internal Medicine, Division of Gastroenterology, Long Island Jewish Hospital, Albert Einstein College of Medicine
Disclosure: Nothing to disclose.
Mohammad K Ismail, MD, AGAF Associate Professor, Department of Internal Medicine and Gastroenterology, Program Director for Gastroenterology Fellowship and Training, University of Tennessee Health Science Center
Disclosure: Nothing to disclose.
John Gunn Lee, MD Director of Pancreaticobiliary Service, Associate Professor, Department of Internal Medicine, Division of Gastroenterology, University of California at Irvine School of Medicine
Disclosure: Nothing to disclose.
Caroline Riely, MD Professor, Departments of Medicine and Pediatrics, University of Tennessee Health Science Center College of Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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