para>Acute fatty liver of pregnancy: Rare but serious complication in 3rd trimester. 50% of cases are associated with preeclampsia (6).
Symptoms: nausea, vomiting, headache, fatigue, right upper quadrant or epigastric gain, jaundice
Elevated ALT and AST >300 IU/L but usually <1,000 IU/L; elevated bilirubin
Liver biopsy confirms diagnosis but should not delay treatment.
Early recognition and prompt delivery is key
Recurrence is rare (6)
‚
Pediatric Considerations
Increasing prevalence of NAFLD among children parallels rise in pediatric obesity.
Reports of NAFLD as early as age 2 years and NASH-related cirrhosis as early as age 8 years
Treat with intensive lifestyle modification. Vitamin E may be of possible benefit.
Reye syndrome: fatty liver syndrome with encephalopathy usually following viral illness
Vomiting with dehydration
Confusion, progressive CNS damage
Hepatomegaly with extensive fatty vacuolization
Hypoglycemia (7)
Etiology unknown; viral URIs and drugs (especially salicylates) have been implicated.
Mortality rate: 50%
Treat with mannitol, IV glucose, and FFP.
‚
GENERAL PREVENTION
- Avoid excess alcohol: ≤3 standard drinks/day (men); ≤2 standard drinks/day (women)
- Maintain appropriate BMI.
- Prevention and optimal management of diabetes
- Avoid hepatotoxic medications.
- HAV and HBV vaccination if not immune
- Pneumococcal and annual influenza vaccinations
COMMONLY ASSOCIATED CONDITIONS
Central obesity; HTN; type 2 diabetes; insulin resistance; hyerlipidemia; preeclampsia in pregnancy; CVD; hypothyroidism; hypogonadism; OSA (2) ‚
DIAGNOSIS
- Routine screening not recommended
- Consider NAFLD in patients with asymptomatic aminotransferase elevations (1)[A].
- Can occur with normal AST/ALT levels (1)[A]
- NAFLD has no distinguishing historical/lab features to distinguish from other chronic liver disorders.
- Index of suspicion is higher with risk factors such as metabolic syndrome, insulin resistance, 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 when results are likely to change management.
HISTORY
- Typically asymptomatic
- Possible fatigue and/or abdominal fullness
- Vague right upper quadrant pain
- History of medications, alcohol use, family history
PHYSICAL EXAM
Most common signs (all are infrequent) ‚
- Liver tenderness
- Mild to marked hepatomegaly
- Splenomegaly
- In advanced cases: cutaneous stigmata of chronic liver disease or portal hypertension, for example, palmar erythema, spider angiomata, ascites
DIFFERENTIAL DIAGNOSIS
- Viral hepatitis
- Alcoholic fatty liver
- Drug- or toxin-induced hepatitis
- Metabolic liver disease
- Autoimmune hepatitis
- Celiac disease
- Muscle disease, if nonhepatic cause of elevated enzymes are possible
DIAGNOSTIC TESTS & INTERPRETATION
- Both ALT and AST may be elevated.
- Nonalcoholic, usually ALT:AST >1
- If alcohol-induced, usually AST:ALT ≥2
- 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).
- Serum ferritin (1.5 times normal), alkaline phosphatase (2 to 3 times normal), and total and direct bilirubin may be elevated (1).
- Severity and chronicity are characterized by defects in ability to produce plasma proteins (serum albumin, PT) and thrombocytopenia (1).
- Lipids abnormalities are common and include elevated cholesterol, low-density lipoprotein (LDL), and triglyceride and decreased HDL (1).
- Biomarkers of inflammation, increased oxidative stress, or hepatocyte apoptosis such as leptin, adiponectin, CRP, serum caspase, and cytokeratin 18 may help differentiate NASH from NAFLD (1)[B].
- Serologic studies to exclude other etiologies of liver disease, for example, celiac,α-1-antitrypsin, iron, copper, HepA IgG, HepB SAg, HepC SAb, anti-smooth muscle antibody, ANA, serum gammaglobulin (1)[B]
- Ultrasound (US) is first-line imaging modality for assessing liver chemistry abnormalities: fatty liver is hyperechoic on US. MRI/CT may also be used (1)[B].
Follow-Up Tests & Special Considerations
- Imaging modalities such as FibroScan (which detects tissue elasticity in cases of suspected hepatic fibrosis) and MR spectroscopy (to assess changes in hepatic fat) are currently being evaluated to better characterize NAFLD (8)[B].
- No imaging modality can distinguish simple steatosis from steatohepatitis.
Diagnostic Procedures/Other
- Liver biopsy is the gold standard for diagnosis. To perform procedure, biopsy must have likelihood of changing management (1)[B].
- NAFLD fibrosis score age (>50 years), BMI (>30), platelet count, albumin, and AST/ALT ratio identifies patients at risk of developing fibrosis/cirrhosis (9)[B].
Test Interpretation
- Liver biopsy is the gold standard for prognosis (1).
- In NASH, steatosis, ballooning, and lobular inflammation are minimal criteria for diagnosis. Other common findings include mild to moderate portal inflammation, acidophil bodies, perisinusoidal zone 3 fibrosis, megamitochondria, and Mallory-Denk bodies (hyaline) in hepatocytes (1).
- Staging is based largely on the extent of fibrosis (1).
TREATMENT
- Sustained weight loss through lifestyle modification of at least 3 " “5% of body weight is most successful treatment (1,9)[A].
- Foregut bariatric surgery not yet proven to specifically treat NASH (1)[B]
- Aerobic exercise 3 to 5 times weekly for 20 to 45 minutes with reduced calorie intake/diet modifications (1)[B]
- Tight control of diabetes (1,9)[B]
- Treatment of metabolic syndrome " ”hypertension, dyslipidemia, and obesity (1,9)[B]
- Limit alcohol consumption (<21 drinks/week for men and <14 drinks/week for women) (9)[A].
- Avoid hepatotoxic medications (1)[B].
MEDICATION
Currently no effective medication treatment (1,9)[A] ‚
Several promising agents include the following: ‚
- Thiazolidinediones (pioglitazone) (1)[B]
- Vitamin E (1)[B]
- Other drugs studied in small studies (1,9,10)[B,C]
- Statins, but study excluded cases with AST and AST >1.5 times normal limit
- Gemfibrozil; omega-3 fatty acids
- Angiotensin receptor blockers; probiotics
- Obeticholic acid (bile acid derivative)
- Ursodeoxycholic acid
ISSUES FOR REFERRAL
Persistent AST/ALT elevations 2 to 3 times above upper limit of normal without diagnosis or those with fibrosis on biopsy benefit from hepatology evaluation (1)[A]. ‚
SURGERY/OTHER PROCEDURES
Bariatric procedures: NAFLD is not a contraindication in otherwise eligible obese patients. There is a lack of data to definitively assess benefits and harms of surgery in treating patients with NASH (1)[B]. ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Annual monitoring of LFTs (1,9)[B]
- Consider surveillance monitoring with US or CT scan to evaluate disease progression/improvement (9)[B]. Improvements can provide motivation for ongoing lifestyle changes.
- Routine liver biopsy is not recommended but may be repeated 5 years after baseline biopsy if progression of fibrosis is suspected (1,9)[B].
- Hepatic fibrosis staging is the strongest predictor for all-cause and disease-specific mortality in patients with histologically confirmed NAFLD (2)[B].
DIET
Low in saturated and trans fat; low in simple carbohydrates; avoid excessive alcohol (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 NALFD, only NASH has been shown to be progressive, potentially leading to cirrhosis, hepatocellular carcinoma, cholangiocarcinoma, and/or liver failure (11): ‚
- Cirrhosis develops in up to 15 " “20% of patients. Approximately 2 " “3% of patients with cirrhosis will develop HCC each year (3).
- Transplantation is effective, but NASH may recur after transplantation 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
11 Chalasani ‚ N, Younossi ‚ Z, Lavine ‚ JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592 " “1609.22 Byrne ‚ CD, Targher ‚ G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1)(Suppl):S47 " “S64.33 Spengler ‚ EK, Loomba ‚ R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clin Proc. 2015;90(9):1233 " “1246.44 Sharma ‚ M, Mitnala ‚ S, Vishnubhotla ‚ RK, et al. The riddle of nonalcoholic fatty liver disease: progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis. J Clin Exp Hepatol. 2015;5(2):147 " “158.55 Than ‚ NN, Newsome ‚ PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis. 2015;239(1):192 " “202.66 Ahmed ‚ KT, Almashhrawi ‚ AA, Rahman ‚ RN, et al. Liver diseases in pregnancy: diseases unique to pregnancy. World J Gastroenterol 2013;19(43):7638 " “7646.77 Hurwitz ‚ ES, Nelson ‚ DB, Davis ‚ C, et al. National surveillance for Reye syndrome: a five-year review. Pediatrics. 1982;70(6):895 " “900.88 Browning ‚ JD. New imaging techniques for non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13(4):607 " “619.99 Nascimbeni ‚ F, Pais ‚ R, Bellentani ‚ S, et al. From NAFLD in clinical practice to answers from guidelines. J Hepatol. 2013;59(4):859 " “871.1010 Ratziu ‚ V, Goodman ‚ Z, Sanyal ‚ A. Current efforts and trends in the treatment of NASH. J Hepatol. 2015;62(1)(Suppl):S65 " “S75.1111 White ‚ DL, Kanwal ‚ F, El-Serag ‚ HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10(12):1342 " “1359.e2.
ADDITIONAL READING
- Rinella ‚ ME. Nonalcholic fatty liver disease: a systematic review. JAMA. 2015;313(22):2263 " “2273.
- Schwimmer ‚ JB, Pardee ‚ PE, Lavine ‚ JE, et al. Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation. 2008;118(3):277 " “283.
- Thoma ‚ C, Day ‚ CP, Trenell ‚ MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012;56(1):255 " “266.
SEE ALSO
Alcohol Abuse and Dependence; Cirrhosis of the Liver; Diabetes Mellitus, Type 2; Metabolic Syndrome ‚
CODES
ICD10
K76.0 Fatty (change of) liver, not elsewhere classified ‚
ICD9
571.8 Other chronic nonalcoholic liver disease ‚
SNOMED
197315008 Non-alcoholic fatty liver (disorder) ‚
CLINICAL PEARLS
- NAFLD: major cause of liver disease. Spectrum ranges from NAFL to NASH, advanced fibrosis, and cirrhosis.
- NAFLD: most common chronic liver disease in children; parallel rise in childhood obesity and NAFLD
- Lifestyle changes with targeted weight loss are the cornerstones of therapy for NAFLD.
- NAFLD is a common cause of asymptomatic mild serum aminotransferase elevation.