History and exam
Key diagnostic factors
common
presence of risk factors
Obesity, insulin resistance or diabetes, hyperlipidaemia, hypertension, metabolic syndrome, history of rapid weight loss, medications, and total parenteral nutrition are known risk factors for non-alcoholic fatty liver disease.
absence of significant alcohol use
Alcohol use should be excluded as the cause of SLD. Varying levels of significant alcohol intake have been suggested.[40] A standard drink contains 14 g of pure alcohol. The American Association for the Study of Liver Diseases defines mild alcohol intake as up to 20 g/day in women and up to 30 g/day in men, moderate alcohol intake as 21-39 g/day in women and 31-59 g/day in men, and heavy alcohol intake as ≥40 g/day in women and ≥60 g/day in men.[3] Asia-Pacific guidelines define significant alcohol consumption as >140 g/week in men and >70 g/week in women.[8] European guidelines define significant alcohol consumption as ≥30 g/day in men and ≥20 g/day in women.[41] Alcohol intake should be verified by more than one healthcare worker and on separate occasions to ensure consistency.
mild abnormality in liver function tests
The most common presentation is mild abnormality in liver function tests with elevation of alkaline phosphatase, aminotransferases, or bilirubin during a work-up for hypertension, diabetes, or obesity.
truncal obesity
Obesity that preferentially affects or is located in the trunk of the body as opposed to the extremities. Distribution of fat in the trunk or central locations is a risk factor for fatty liver even in patients with a normal body mass index.[22]
Other diagnostic factors
common
fatigue and malaise
Probably the most commonly reported initial symptoms in patients with metabolic dysfunction-associated steatotic liver disease (MASLD); does not seem to correlate with severity of disease.[37]
right upper quadrant abdominal discomfort
May be an initial presenting symptom in patients with MASLD.[38] Sometimes related to hepatosplenomegaly, but often there is no identifiable aetiology.
hepatosplenomegaly
Up to 50% of patients with MASLD will have an enlarged liver upon presentation of their disease.[39]
uncommon
signs of chronic liver disease
These include jaundice, altered mental status (due to hepatic encephalopathy), ascites, peripheral oedema, spider angiomata, palmar erythema, clubbing, nail changes, Dupuytren's contracture, bruising, petechiae, gynaecomastia, excoriations (secondary to pruritus), parotid gland enlargement, alopecia, testicular atrophy, asterixis, low blood pressure, fetor hepaticus, and caput medusae. More likely to occur with metabolic dysfunction-associated steatohepatitis (MASH); the risk of metabolic dysfunction-associated steatotic liver (MASL) progressing to cirrhosis or liver failure is minimal.[3]
See Cirrhosis.
Risk factors
strong
obesity
Increased fat mass is an essential pathophysiological factor in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Not all fat seems to be the same. Distribution of fat is important, with centrally located obesity being a higher risk factor for the development of MASLD.[21] This may explain the subgroup of patients with normal BMI and central obesity who have MASLD.[22] The likelihood of developing MASLD increases with the degree of obesity. The prevalence of MASLD has been shown to be as high as 93% in patients with class 3 obesity undergoing bariatric surgery.[23]
insulin resistance or diabetes
Insulin resistance has been shown in both clinical and laboratory-based studies to play a key role in MASLD. It is regarded as the hallmark and causal factor even in the absence of obesity and diabetes mellitus. Overt diabetes and insulin resistance (as defined by the homeostatic model assessment [HOMA] criteria of ≥2) are frequently observed in patients with MASLD. Up to 63% of people with diabetes have MASLD.[23] Routinely available clinical variables can be used to help determine the likelihood of disease severity in diabetic patients with MASLD.[24] Insulin resistance has also been observed in patients with MASH who are not obese and in those who have normal glucose tolerance.[25]
dyslipidaemia
hypertension
There is a higher prevalence of fatty liver in hypertensive patients without risk factors for SLD. Fatty liver was present in 30% of cases in one study, a prevalence almost 3 times higher than age- and sex-matched normotensive controls.[27]
metabolic syndrome
Many patients with MASLD fulfil criteria for metabolic syndrome, including fasting hyperglycaemia, high blood pressure, central obesity, decreased HDL cholesterol, and elevated triglycerides.
Patients with MASH are more likely to have metabolic syndrome than those with simple steatosis.[28] A prospective observational study of Japanese men showed that the presence of metabolic syndrome confers a 4- to 11-fold increased risk for future development of MASLD.[29] Most experts now consider fatty liver as the hepatic manifestation of metabolic syndrome.[19]
rapid weight loss
Rapid weight loss in a short period of time is a risk factor for the development of fatty liver. This link was first made in patients undergoing jejuno-ileal bypass.[18][28] Hepatic abnormalities, most notably the development of MASH, may persist or progress despite reversal in more than one third of patients.[30]
medications
Medications associated with the development of SLD include tamoxifen, corticosteroids, diltiazem, nifedipine, methotrexate, valproate, griseofulvin, intravenous tetracycline, amiodarone, and antiretroviral therapy for HIV.
Examples of drugs associated with a pure microvesicular histological phenotype are aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, valproate, tetracycline, nucleoside reverse-transcriptase inhibitors, and cocaine. Drugs associated with a macrovesicular histological phenotype include NSAIDs, corticosteroids, methotrexate, metoprolol, fluorouracil, cisplatin, irinotecan, tamoxifen, and chlorinated hydrocarbons. A mixed macrovesicular and microvesicular histological phenotype may be associated with drugs such as amiodarone, valproate, and methotrexate. Drugs including amiodarone, methotrexate, fluorouracil, cisplatin, irinotecan, and tamoxifen may also be associated with a steatohepatitic histological phenotype.[31]
Long-term methotrexate treatment, in particular, is associated with the development of SLD and fibrosis, particularly in the presence of other known risk factors (obesity, alcohol consumption, pre-existing liver disease, diabetes, hyperlipidaemia).[31]
total parenteral nutrition (TPN)
TPN is a risk factor for an array of gastrointestinal and hepatobiliary complications ranging from benign steatosis to liver failure. TPN is associated with the development of SLD in 40% to 55% of adults.[32]
weak
diseases associated with SLD
Rates of MASLD occurrence are higher in patients with hypothyroidism, hypogonadism, growth hormone deficiency, and polycystic ovarian syndrome.[3]
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