NASH Resource Center

Basics

• A spectrum of fatty liver diseases ranging from nonalcoholic fatty liver (NAFL), to nonalcoholic steatohepatitis (NASH), to fibrosis and cirrhosis, not due to other cause of fatty infiltration of liver (such as alcohol use)
• Most common chronic liver disease in the United States and other industrialized nations; implicated in up to 90% of patients with asymptomatic, mild aminotransferase elevation not caused by alcohol, viral hepatitis, or medications

Description

• NAFL (1)
  • Reversible condition in which large vacuoles of triglyceride fat accumulate in hepatocytes
  • Liver biopsy: fatty deposits in cells without hepatocellular injury (no hepatocyte ballooning, no necrosis, no fibrosis)
  • ALT and AST normal or ,3 to 4 ULN – Minimal risk of progressing to cirrhosis or liver failure
  • Synonym: steatosis
• NASH: progressive form of NAFL (1)
  • Liver biopsy: fatty deposits in cells with hepatocellular injury (ballooning, acute/chronic inflammation, 6 fibrosis); may be histologically indistinguishable from alcoholic steatohepatitis
  • ALT and AST elevated, generally ,3 to 4 ULN
  • 30% with NASH may progress to fibrosis over 5 years and may progress to cirrhosis, liver failure, and rarely hepatocellular cancer
• NASH cirrhosis: presence of cirrhosis with current or previous histologic evidence of steatosis or steatohepatitis

Epidemiology

• Most common chronic liver disease in industrialized Western countries
• Predicted to become the most frequent indication for liver transplantation by 2030 (2)
• Predominant age: 40s to 50s; can occur in children
• Predominant sex: male = female

Incidence

Estimates vary widely from 31 to 86 cases of NAFLD per 10,000 person-years to 29/100,000 person-years (1).

Prevalence

• United States estimate: 10–46%
• Present in 58–74% of obese (BMI $30 kg/m2 ); 90% of morbidly obese (BMI $40 kg/m2 ); 69–87% with type 2 DM; 50% with dyslipidemia (1)

Etiology and Pathophysiology

Primary mechanism is thought to be insulin resistance, leading to increased lipolysis, triglyceride synthesis, and increased hepatic uptake of fatty acids.Thus, there is international momentum to rename this condition metabolic-associated fatty liver disease (MAFLD).

• NAFL: excessive triglyceride accumulation in the liver and impaired ability to remove fatty acids
• NASH: multiple hit theory (insulin resistance, adipose tissue hormones, oxidative stress damage, genetic factors, intestinal bacteria) that causes inflammation and acts on liver parenchymal cells leading to steatohepatitis

Genetics

• Largely unknown: some familial clustering and increased heritability
• NAFL: more first-degree relatives with cirrhosis than matched controls
• NASH: 18% with affected first-degree relative (1)

Risk Factors

• Obesity (BMI .30 kg/m2 ), visceral obesity (waist circumference .102 cm for men or .88 cm for women), hypertension, high triglycerides and low high-density lipoprotein (HDL) levels, metabolic syndrome
• Type 2 diabetes mellitus (DM), cardiovascular disease, and chronic kidney disease
• Protein–calorie malnutrition; total parenteral nutrition (TPN) .6 weeks
• Severe weight loss (starvation, bariatric surgery)
• Organic solvent exposure (e.g., chlorinated hydro- carbons, toluene); vinyl chloride; hypoglycin A
• Gene for hemochromatosis/other conditions with increased iron stores
• Smoking
• Drugs: tetracycline, glucocorticoids, tamoxifen, methotrexate, amiodarone, antiretroviral agents for HIV, valproic acid, fialuridine, many chemotherapy regimens, nucleoside analogues
• History of cholecystectomy
• Increasing age associated with increased prevalence, severity, advanced fibrosis, and mortality Pregnancy Considerations Acute fatty liver of pregnancy: rare but serious compli- cation in 3rd trimester—50% of cases are associated with preeclampsia

Pregnancy Considerations

Acute fatty liver of pregnancy: rare but serious complication in 3rd trimester—50% of cases are associated with preeclampsia

Pediatric Considerations

• Pediatric NAFLD
  • Increasing prevalence of NAFLD among children parallels rise in pediatric obesity, with prevalence of 9.6% (1)
  • Vitamin E of possible benefit
• Reye syndrome: fatty liver syndrome with encepha- lopathy usually following viral illness and aspirin use

General Prevention

• Avoid excess alcohol: #2 units per day (men); #1 unit per day (women). One unit equals 10 mL or 8 g of pure alcohol, which is around the amount of alcohol the average adult can process in an hour. 1 shot of spirits 5 1 unit; 12 oz beer 5 ,1.7 units; glass of wine 5 2 units.
• Maintain appropriate BMI.
• Prevention and optimal management of diabetes
• Avoid hepatotoxic medications.

Commonly Associated Conditions

Central obesity; hypertension; type 2 diabetes; insulin resistance; hyperlipidemia; preeclampsia in pregnancy; CVD and arrhythmias; hypothyroidism; hypogonad- ism; OSA; chronic kidney disease; growth hormone deficiency; polycystic ovary syndrome (1)

Diagnosis

• Consider NAFLD in patients with asymptomatic aminotransferase elevations (1)[A].
• NAFLD has no distinguishing historical/lab features to differentiate from other chronic liver disorders.
• Index of suspicion is higher with risk factors, such as metabolic syndrome or obesity
• May present as cryptogenic cirrhosis • Noninvasive biomarkers of steatosis/fibrosis are not sufficiently reliable.
• Liver biopsy is the definitive diagnostic test but should only be considered if results will change management.

History

• Typically asymptomatic
• Possible fatigue and/or abdominal fullness
• Vague right upper quadrant pain
• History of medications, family history

Physical Exam

Usually normal, but signs may include the following:

• Liver tenderness
• Mild to marked hepatomegaly
• Splenomegaly
• In advanced cases: cutaneous stigmata of chronic liver disease or portal hypertension (e.g., palmar erythema, spider angiomata, ascites); jaundice

Differential Diagnosis

• Viral hepatitis; drug- or toxin-induced hepatitis; autoimmune hepatitis
• Alcoholic liver disease
• Celiac disease
• Muscle disease, if nonhepatic cause of elevated enzymes is possible
• Hemochromatosis; Wilson disease; lipodystrophy

Diagnostic Tests & Interpretation

The diagnosis of NAFLD (2) requires:

• Demonstration of hepatic steatosis by imaging or biopsy
• No history of significant alcohol consumption
• Exclusion of other causes of hepatic steatosis
• Absence of coexisting chronic liver disease

Initial Tests (lab, imaging)

• ALT and AST may be elevated.
  • Nonalcoholic, usually AST/ALT ,1
  • Nonspecific enzyme abnormalities may exist or may be normal with advanced cirrhosis (1).
  • Level of enzyme elevation does NOT correlate with degree of fibrosis (1).
• Elevated ferritin (1.5 times normal)
• Elevated alkaline phosphatase, total/direct biliburin
• Lipid abnormalities: elevated total cholesterol, elevated LDL, elevated triglycerides, decreased HDL
• If cirrhosis present: decreased serum albumin, elevated PT, thrombocytopenia • Serum labs to exclude other causes of liver disease: celiac, α1-antitrypsin, iron, copper, hepatitis serolo- gies, anti-smooth muscle antibody,ANA, serum γ-globulin (1)[B]
• Ultrasound (US) is first-line imaging: fatty liver appears hyperechogenic (1)[B].

Follow-Up Tests & Special Considerations

Other modalities can help noninvasively quantify fibrosis by estimating liver stiffness, but no modality accurately distinguishes simple steatosis from steato- hepatitis (1).

• Clinical decision aids: NAFLD fibrosis score, FIB-4 index,APRI score (2)
• Serum biomarkers: enhanced liver fibrosis panel, FibroTest, HepaScore
• Imaging: vibration controlled transient elastogra- phy (VCTE) or FibroScan, acoustic radiation force impulse (ARFI), magnetic resonance elastography (MRE, most reliable measurement, but expensive)

Diagnostic Procedures/Other

Liver biopsy: gold standard for diagnosis and prognosis—must have likelihood of changing management prior to biopsy (1)[B]

Test Interpretation

• NAFLD activity score (NAS): used to grade diagnosis, based on three histologic features: steatosis (0 to 3), inflammation (0 to 3), and hepatocyte ballooning (0 to 2), for score between 0 and 8. NASH is very likely with scores $5.
• Steatosis Activity Fibrosis: staging scale (0 to 4) based on degree of fibrosis (1)

Treatment

Emphasis on early management of metabolic risk fac- tors, NAFLD associated with increased cardiovascular morbidity and mortality

General Measures

• Weight loss for those who are overweight or obese is the only therapy that has good evidence of benefits and safety.Aim for sustained weight loss (5–10% body weight) (1).
• Diet modification: Mediterranean diet has been shown to reduce liver fat (1). Avoid or limit alcohol consumption.
• Aerobic exercise 5 times per week for a total of 150 minutes per week (1)[B]
• Tight diabetes control (1) • Treat metabolic syndrome—hypertension, dyslipidemia, and obesity
• Vaccination for hepatitis A and B for those nonimmune
• Pneumococcal and annual influenza vaccinations
• Avoid hepatotoxic medications (1)[B].

Issues for Referral

Refer to hepatology if persistent AST/ALT elevations, advanced fibrosis (stage F3 or greater) on liver scan, or fibrosis on liver biopsy (1)[A].

Surgery/Other Procedures

• Bariatric surgery: may be considered in obese pa- tients with NAFLD, NASH, or advanced fibrosis who do not achieve weight loss goals after adequate trial of lifestyle modifications.
• Liver transplant: NAFLD is second most common cause for liver transplant; however, NAFLD will recur in the transplanted liver in 80–100% of patients.

Ongoing Care

Follow-Up Recommendations

• Annual monitoring of LFTs (1)
• Surveillance with US or CT to evaluate for disease progression every 2 to 4 years, or sooner if increas- ing metabolic risk factors
• Routine liver biopsy is not recommended but may be repeated 5 years after baseline biopsy if progression of fibrosis is suspected (1).
• Hepatic fibrosis staging is the strongest predictor for mortality in patients with histologically confirmed NAFLD (2).
• Screening for hepatocellular carcinoma in noncirrhotic NAFLD is yet to be determined (2).

Diet

Low in saturated and trans fat; low in simple carbohy- drates; avoid excessive alcohol or abstinence preferred (protective or worsening effect of light/moderate consumption inconclusive).

Patient Education

Extensive counseling on sustained lifestyle changes in nutrition, exercise, and alcohol use

Prognosis

Within the spectrum of NAFLD, only NASH has been shown to be progressive, potentially leading to cir- rhosis, hepatocellular carcinoma, cholangiocarcinoma, and/or liver failure.

• Cirrhosis develops in up to 20% of patients. Up to 42% of patients develop hepatocellular carcinoma without showing cirrhosis.
• Transplantation is effective, but NASH often recurs after due to ongoing risk factors.

Complications

Progressive disease may lead to decompensated cirrhosis and portal hypertension with complications such as ascites, encephalopathy, bleeding varices, and hepatorenal or hepatopulmonary syndromes.

References

1. Chalasani N,Younossi Z, Lavine JE, et al.The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver diseases. Hepatology. 2018;67(1):328–357.
2. Ando Y, Jou JH. Nonalcoholic fatty liver disease and recent guideline updates. Clin Liver Dis (Hoboken). 2021;17(1):23–38.
3. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797–1835.

Additional Reading

Kumar R, Priyadarshi RN,Anand U. Non-alcoholic fatty liver disease: growing burden, adverse outcomes and associations. J Clin Transl Hepatol. 2020;8(1):76–86.

See Also

• Alcohol Use Disorder (AUD); Cirrhosis of the Liver; Diabetes Mellitus,Type 2; Metabolic Syndrome
• Algorithm: Weight Loss,Treatment

Codes

ICD10
K76.0 Fatty (change of) liver, not elsewhere classified

Clinical Pearls

• NAFLD is a major cause of liver disease, and is increasing every year with increasing rates of over- weight and obesity.
• Spectrum ranges from NAFL to NASH, advanced fibrosis, and cirrhosis.
• NAFLD is the most common chronic liver disease in children; there has been a parallel rise in childhood obesity and NAFLD.
• Lifestyle changes with targeted weight loss are the cornerstones of therapy for NAFLD.