Nonalcoholic fatty liver disease (NAFLD)

It has become one of the leading causes of cirrhosis and hepatocellular carcinoma in middle and high income countries with an estimated annual direct medical cost of approximately $103 billion in the US.

Defined is hepatic steatosis, either by imaging or histology, in the absence of alcohol abuse, medications, or other causes for fatty liver disease.

Non-alcoholic steatohepatitis (NASH) is the association of steatosis with hepatocyte injury or with inflammation.

NAFLD encompasses a wide spectrum of pathology from simple steatosis to NASH an entity associated with advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma.

MASLD has a dose response relationship between the severity of liver fibrosis and future risk of liver related events.

NAFLD can progress to NASH if metabolic factors deteriorate, and NASH can revert with treatment.

Approximately 20 to 25% of individuals with NAFLD a predicted to have NASH, accounting for 5% of the US adult population.

Prevalence of an NAFLD in US adult approaches 40%.

Fewer than 5% of patients with NALD are aware of their condition, and 12 to 14% also have NASH, which can progress to advanced liver, fibrosis, cirrhosis, and hepatocellular carcinoma.

Estimated 75-100,000,000 US have NAFLD.

More than 75% of patients with NAFLD are undiagnosed in the community.

NAFLD affects more than 1/4 of the adult population globally. 

It is closely linked to underlying obesity, type two diabetes, and related disorders.

Affects approximately 70% of people with obesity or type two diabetes.

It’s histologic spectrum ranges from nonalcoholic fatty liver to non-alcoholic steatohepatitis (NASH).

Overall prevalence of 19 – 46%.

NAFLD affects a quarter of the worlds adult population.

Type two diabetes is a strong predictor for the development of NAFLD, advanced fibrosis, and hepatocellular carcinoma.

Affects about 25% of the adult population globally and strongly associated with metabolic syndrome, affecting most patients who have dyslipidemia, obesity, or type two diabetes

Presently is the most common cause of liver disease and predicted to be the main indication for liver transplantation.

Its histologic spectrum ranges from nonalcoholic fatty liver to non-alcoholic steatohepatitis (NASH).

Studies of steatosis found platelets are the first cells to infiltrate the liver, promoting inflammation, by activating Kupfer cells and releasing pro inflammatory alpha granules.

NAFLD has become the most common cause of chronic liver disease in adults, even in children, and it is the second leading indication for liver transplantation behind hepatitis C disease.

There are about 18.2 million people in the US living with type two diabetes and NAFLD of which 37% of believed to have NASH.

Fibrosis stages F3 and F4 are associated with increased risk of liver related complications and death.

Cardiovascular disease is the leading cause of death associated with NAFLD.

NASH is a progressive form of NAFLD and has superseded hepatitis  as the main cause of cirrhosis and the main reason for liver transplantation..

Chronic liver disease that may progress to cirrhosis and is characterized by accumulation of hepatic fat, insulin resistance and lobular necro-inflammation, with or without centrilobular fibrosis.

It is associated with an overall higher mortality, which increases exponentially with fibrosis stage.

Insulin resistance is associated with ectopic lipid deposition in skeletal muscle and liver.

A complex process involving the progression from simple steatosis to inflammation and then to severe fibrosis and hepatocellular carcinoma, which are the major predictors of death in patients with this disease.

Complex disease affected by metabolic, genetic, environmental and gastrointestinal microbiota.

Typical features of the disease are type 2 diabetes, obesity and fatty liver disease.

Most common cause of persistently abnormal liver tests.

Increasing in frequency.

Incidence parallels that of obesity and diabetes.

Much more prevalent in individuals with type two diabetes not previously treated with insulin compared with those treated with insulin 75.6 vs 61.7%.

Liver fat content is greater in type two diabetics not previously treated with insulin compared with persons with insulin treated type two diabetes or those with type one diabetes.

In patients with type one or type two diabetes the mean body mass index is associated with elevated liver fat content.

In type two diabetes the mean fasting glucose level, triglyceride level, and transaminase level are higher among those with NAFLD.

Most common cause of liver disease worldwide prevalence from 25-45%.

About 2-7% of those with non-alcoholic fatty liver disease have evidence of non-alcoholic steatohepatitis on liver biopsy, with liver inflammation and injury.

Long-standing nonalcoholic fatty liver disease and non-alcoholic steoatohepatitis can result in cirrhosis and its complications, including hepatocellular carcinoma.

There is no association between hemoglobin A1 C levels and liver fat content, but insulin requirements are higher in person to have NAFLD.

Consists of simple fatty liver, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease-associated cirrhosis.

Nonalcoholic steatohepatitis ranks as the second most common reason for liver transplant in the US and will likely surpass hepatitis C in the coming years.

An important component of metabolic syndrome.

In general obesity, positive family history of diabetes, and male gender are risk factors for NAFLD.

Much more prevalent in patients with type 2 diabetes, reaching approximately 70%, than in patients with type 1 diabetes, approximately 8.8%.

Two thirds of patients older than 50 years with diabetes or obesity have nonalcoholic steatohepatitis.

The most common indication for liver transplantation in the US.

Patients  with MASLD and type 2 diabetes or those with multiple components of the metabolic syndrome are at greater risk for development of adverse clinical liver events.

Most patients are asymptomatic.

75% have hepatomegaly.

80% have elevated LFTs.

Diagnosis is based on the presence of hepatic steatosis in more than 5% of hepatocytes, absence of significant alcohol consumption, exclusion of the presence of other liver diseases.

Screening for NAFLD include patients with obesity, persistently elevated amino transferases, hepatic steatosis on imaging, and patients with cardiometabolic diseases.

There is a dose response relationship between the severity of liver fibrosis and future risk of liver related events.

Liver stiffness measurement by vibration controlled transient elastography reflects the degree of liver fibrosis, and also predicts hepato cellular carcinoma, portal hypertension, and varices.

By combining liver stiffness measurement, and clinical parameters, such as platelet count, ALT, diabetes, age, and sex an Agile score can improve accuracy and improve prognosis scores.

Vibration controlled transient elastography based scores are generally accurate for predicting liver related events, making them suitable alternatives to live biopsy in routine clinical practice for patients with steatohepatitis (VCTE prognosis study group).

FIB-4 index can be used to assess fibrosis and includes age, platelet count, AST, ALT, which predicts risk of hepatic cirrhosis and other liver related adverse events in adults.

The majority of patients with NAFLD, have AST and ALT levels of less than 40.

Histologically categorized into nonalcoholic fatty liver, including isolated hepatic steatosis and steatosis with mild nonspecific inflammation and nonalcoholic steatohepatitis with features of hepatocellular injury with or without fibrosis.

NAFLD and subtype nonalcoholic steatohepatitis affects 30% and 5%, respectively, of US population.

Estimated between 30-40% of the population, that is 80 to 100,000,000 Americans is affected by NAFLD.

NAFLD is becoming the most common liver disease in children.

Pediatric NAFLD is more common in boys than girls, and Hispanic children compared with other races and ethnic cities.

The presence of liver fibrosis the most important determinant of outcome.

Nonalcoholic steatohepatitis (NASH), a subtype of NAFLD, can be complicated by cardiovascular disease, cirrhosis and hepatocellular carcinoma.

Metavir scoring system is used ranging from 0-stage 4, the latter indicating cirrhosis.

Approximately 20% of patients with nonalcoholic steatohepatitis progressed to advanced fibrosis and cirrhosis.

Nonalcoholic fatty liver has a more benign disease with an estimated 4% progression to cirrhosis.

NAFLD categorized into 2 subtypes:NAFLD which is usually non progressive, and NASH which is often progressive and can lead to cirrhosis and hepatcellular cancer.

The two disorders are a spectrum of disease.

Liver ultrasound is the most commonly used diagnostic modality and typically shows increased echogenecity of the liver parenchyma consistent with hepatic steatosis.

Liver ultrasound can detect moderate to severe steatosis, defined as fat droplets in more than 33% of liver, with the sensitivity and specificity of approximately 90%.

ALT levels usually greater than AST levels, in contrast to alcoholic liver disease.

Serum ferritin levels commonly elevated.

15% of caases can progress to cirrhosis.

Increased risk of mortality from liver disease at 13%, cardiovascular disease at 25%, and malignancy at 28%.

 NAFLD and NAS hepatic disorders lead to pro inflammatory transformation of epicardial adipose tissue, causing derangements of the adjoining myocardium and result in atrial fibrillation and heart failure with preserved ejection fraction.

NAFLD is an independent risk factor for the development of heart disease: risk factors such as insulin resistance, hypertension, dyslipidemia are common and likely strong contributors to increase cardiovascular risk.

Dyslipidemia is thought to be secondary to insulin resistance associated with steatosis, with decreased HDL cholesterol, elevated triglycerides, smaller low density lipoprotein cholesterol particle size, and an elevated number of apolipoprotein B particles.

Patients with NAFLD, should receive treatment for obesity, insulin resistant/pre-diabetes, dyslipidemia, and hypertension.

Diet modifications and physical activity are first line therapy in people with excess adiposity and goals are sustained weight loss.

A 5% weight loss is correlated with a 30% relative reduction in intrahepatic triglyceride content.

A weight loss goal of at least 5% or preferably 10%, is associated with decreased hepatic steatosis, resolution of NASH, and reduction in hepatic fibrosis and improves cardiometabolic parameters.

Interventions in NAFLD and NASH liver disease that can ameliorate fat mediated information include: statins, Metformin, sodium glucose transporter 2  inhibitors, glucagon like peptide-1 receptor agonist and pioglitazone.

Pharmacotherapy for obesity is considered in obesity, diabetes, and NAFLD, and treatment with Semaglutide tirezepatide can reduce hepatic steatosis.

Associated with increased incidence of colon adenomas and greater risk of adnanced colon neoplasia.

Weight loss is the standard treatment.

No current drug treatment has proven to be beneficial.

Insulin resistance frequently associated with chronic hyperinsulinism, hyperglycemia, and increased supply of free fatty acids in the liver promoting hepatic lipogenesis.

Visceral adipose tissue alters lipid and glucose metabolism leading to liver fat accumulation and a pro inflammatory process triggering hepatocellular and other tissue damage.

Frequently associated with metabolic syndrome with obesity, hypertriglyceridemia and type 2 diabetes.

Patients have low plasma adiponectin levels and adiponectin receptor expression in the liver.

Oxidative stress a key factor that can contribute to hepatic injury (McClain CJ).

Pilot studies indicated that insulin sensitizers such as thiazolidinediones and antioxidants vitamin E improved histlogical changes of nonalcoholic steatohepatitis.

Rosiglitazone trial improved hepatic steatosis, but no improvement in cell injury markers was noted (Ratzui V).

In a phase III trial of 247 adults with nonalcoholic steatohepatitis and without diabetes were randomized to pioglitazone, vitamin E or placebo:vitamin E compared to placebo was associated with a significantly higher rate of improvement of nonalcoholic steatohepatitis 43% vs 19%, and pioglitazone was not beneficial compared to placebo.

Mainstay of therapy is lifestyle modification, but most patients do not achieve or maintain dietary goals and weight loss.

NAFLD management includes treatment of the disease liver, and concurrent metabolic issues such as dyslipidemia, diabetes, and visceral obesity.

The management of NAFLD is multimodal approach with weight loss and exercise, decreasing the risk of cardiovascular events, and reducing heavy alcohol consumption.

Lipid lowering medications show significant improvement in serum aminotransferases and decreased incidence of cardiovascular events in patients with NAFLD.

Weight loss is the cornerstone o NAFLD management with histologic hepatic improvement occurring with 5 to 10% of body weight reduction.

Liraglutide is safe, well tolerated and leads to histological resolution of nonalcoholic steatohepatitis.

In patients with metabolic dysfunction associated steatotic liver disease, low dose daily aspirin significantly reduced hepatic fat compared with placebo.