History

Fact Explanation
Asymptomatic Most patients are asymptomatic during the early stages. Some may present with symptoms like fatigue. [2,3]
Right upper quadrant pain Patients sometimes complain of vague right upper quadrant pain, fullness or discomfort. [2,3]
Symptoms of cirrhosis Since most patients are asymptomatic during the early part of the illness, they might be diagnosed when they develop cirrhosis. Patients present with jaundice, abdominal distension, hematemesis, melena, altered levels of consciousness. [2]
Presence of risk factors Obesity, type 2 diabetes mellitus, metabolic syndrome, hyperlipidemia are risk factors for the development of (Non-Alcoholic Fatty Liver Disease) NAFLD. Treatment with certain drugs (Tamoxifen, Glucocorticoids, Amiodarone, Valporic acid, Zidovudine ) may also cause NAFLD. [2,3]
References
  1. MARCHESINI G, BUGIANESI E, FORLANI G, CERRELLI F, LENZI M, MANINI R, NATALE S, VANNI E, VILLANOVA N, MELCHIONDA N, RIZZETTO M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology [online] 2003 Apr, 37(4):917-23 [viewed 17 May 2014] Available from: doi:10.1053/jhep.2003.50161
  2. TOLMAN KG, DALPIAZ AS. Treatment of non-alcoholic fatty liver disease Ther Clin Risk Manag [online] 2007 Dec, 3(6):1153-1163 [viewed 17 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387293
  3. MAX BAYARD, JIM HOLT, EILEEN BOROUGHS. Nonalcoholic Fatty Liver Disease. Am Fam Physician. [online] 2006 Jun 1;73(11):1961-1968. [viewed 18 May 2014] Available from: http://www.aafp.org/afp/2006/0601/p1961.html

Examination

Fact Explanation
Body Mass Index (BMI) NAFLD is seen in patients with obesity or overweight. [2]
Features suggestive of metabolic syndrome Acanthosis nigricans, obesity, high blood pressure and pheripheral stigmata of hyperlipidemia (xantholesma, xanthomata) should be looked for. [3]
Hepatomegaly Some patients have hepatomegaly. [2]
Signs of cirrhosis [1,2] Cirrhotic patients have ascites, spider nevie, palmer erythema, jaundice, finger clubbing and gynecomasita. If the patient has hepatic encephalopathy hepatic flaps and altered level of consciousness can be detected.
References
  1. TOLMAN KG, DALPIAZ AS. Treatment of non-alcoholic fatty liver disease Ther Clin Risk Manag [online] 2007 Dec, 3(6):1153-1163 [viewed 17 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387293
  2. MAX BAYARD, JIM HOLT, EILEEN BOROUGHS. Nonalcoholic Fatty Liver Disease. Am Fam Physician. [online] 2006 Jun 1;73(11):1961-1968. [viewed 18 May 2014] Available from: http://www.aafp.org/afp/2006/0601/p1961.html
  3. GRUNDY S. M.. Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation [online] 2005 October, 112(17):2735-2752 [viewed 18 May 2014] Available from: doi:10.1161/CIRCULATIONAHA.105.169404

Differential Diagnoses

Fact Explanation
Alcoholic cirrhosis In alcoholic cirrhosis γ-glutamyltransferase are elevated up to about two times normal. Hepatic transaminase levels are usually less than 300 U/L and the ratio of AST/ALT is equal or more than 1. [1]
Viral hepatitis Transaminase levels are often more than 1,000 U/L in acute infection but lower in chronic states. AST/ALT ratio is less than 1. Bilirubin levels are usually elevated. Viral serology, and detection of immunoglobulin against viruses will aid in diagnosis. [1]
Hemochromatsis [1] Iron saturation is increased in hemochromatosis. [2]
Autoimmune hepatitis [1] Common in females and other features of autoimmune diseases may present. Diagnosis is often favored by exclusion of other possible etiologies and by demonstrating the presence of autoantibodies. [3,4] The definitive diagnosis is made according to the diagnostic criteria of the International Autoimmune Hepatitis Group. [3]
Drug induced hepatitis Drug history should be carefully inquired for clues for diagnosis. Elevated hepatic transaminases levels comes to normal once the drug is discontinued. [1]
References
  1. MAX BAYARD, JIM HOLT, EILEEN BOROUGHS. Nonalcoholic Fatty Liver Disease. Am Fam Physician. [online] 2006 Jun 1;73(11):1961-1968. [viewed 18 May 2014] Available from: http://www.aafp.org/afp/2006/0601/p1961.html
  2. ELLERVIK C, TYBJAERG-HANSEN A, NORDESTGAARD BG. Risk of cancer by transferrin saturation levels and haemochromatosis genotype: population-based study and meta-analysis. J Intern Med [online] 2012 Jan, 271(1):51-63 [viewed 16 May 2014] Available from: doi:10.1111/j.1365-2796.2011.02404.x
  3. NAGA C. NORMAN G. ACUTE HEPATITIS A: WHAT'S NEW WITH IT? American Journal of Gastroenterology [online] (1998) 93, 2305–2306; [viewed 16 May 2014] Available from:doi:10.1111/j.1572-0241.1998.02305.x
  4. ALBERT J. C. Autoimmune Hepatitis – Approach to Diagnosis. MedGenMed. [online] 2006; 8(2): 55. [viewed 16 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785222/#!po=8.82353

Investigations - for Diagnosis

Fact Explanation
Hepatic transaminases Both alanine transaminase (ALT) and aspartate transaminase (AST) are elevated (maximum up to four times of the upper limit of normal) but some patients can have normal levels as well. [3] ALT/AST ratio is usually greater than 1in NAFLD.[1]
Alkaline phosphatase Elevated up to about two times of the upper limit of normal. [3]
γ-glutamyltransferase Can be elevated. [3]
Serum triglycerides Usually elevated. [1]
Liver biopsy [1] This is the gold standard in diagnosing NAFLD. Liver biopsy enables the differentiation of non-alcoholic steato-hepatitis (NASH) and NAFLD. However liver biopsy cannot differentiate alcoholic and non-alcoholic fatty liver. [2,4] Considering the risk of biopsy it is recommended only in patients who are likely to have advanced disease(diagnosed patients with diabetes mellitus, dyslipidemia, metabolic syndrome, morbid obesity). [5]
Ultrasound scan Ultrasound scan shows fatty infiltration of the liver. [3] It has a high sensitivity and specificity in diagnosing NAFLD. [2,4]
CT scan Shows fatty infiltration. This is not superior to ultrasound scan in diagnosing NAFLD. [2,3]
Serum albumin Decreased due to reduced hepatic synthesis. Hypoalbuminemia predicts the presence of hepatic fibrosis. [2]
Serum bilirubin [3] Surprisingly serum bilirubin levels are inversely related to the prevalence of NAFLD. [6]
Prothrombin time Prolonged. [2]
Full blood count Thrombocytopenia and anemia occurs with liver fibrosis. [1,2,7]
References
  1. ANGULO P, KEACH JC, BATTS KP, LINDOR KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology [online] 1999 Dec, 30(6):1356-62 [viewed 17 May 2014] Available from: doi:10.1002/hep.510300604
  2. TOLMAN KG, DALPIAZ AS. Treatment of non-alcoholic fatty liver disease Ther Clin Risk Manag [online] 2007 Dec, 3(6):1153-1163 [viewed 17 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387293
  3. MAX BAYARD, JIM HOLT, EILEEN BOROUGHS. Nonalcoholic Fatty Liver Disease. Am Fam Physician. [online] 2006 Jun 1;73(11):1961-1968. [viewed 18 May 2014] Available from: http://www.aafp.org/afp/2006/0601/p1961.html
  4. HULTCRANTZ R., GABRIELSSON N.. Patients with persistent elevation of aminotransferases: investigation with ultrasonography, radionucleide imaging and liver biopsy. [online] 1993 January, 233(1):7-12 [viewed 18 May 2014] Available from: doi:10.1111/j.1365-2796.1993.tb00640.x
  5. ANGULO PAUL, KEACH JILL C., BATTS KENNETH P., LINDOR KEITH D.. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology [online] 1999 December, 30(6):1356-1362 [viewed 18 May 2014] Available from: doi:10.1002/hep.510300604
  6. KWAK MS, KIM D, CHUNG GE, KANG SJ, PARK MJ, KIM YJ, YOON JH, LEE HS. Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease. Clin Mol Hepatol [online] 2012 Dec, 18(4):383-90 [viewed 18 May 2014] Available from: doi:10.3350/cmh.2012.18.4.383
  7. QAMAR AA, GRACE ND. Abnormal hematological indices in cirrhosis Can J Gastroenterol [online] 2009 Jun, 23(6):441-445 [viewed 16 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721814

Investigations - Followup

Fact Explanation
Screening of Hepatocellular carcinoma (HCC) HCC is a recognized complication of NAFLD. [1,2] Serum alpha-fetoprotein and ultrasound scan are cost effective investigation options, but contrast enhanced CT scan and MRI can also be useful. [3,4,5]
Risk assessment of cardiovascular disease [1] NAFLD is an independent risk factor in developing cardiovascular diseases. Lipid profile, fasting blood sugar and ECG are helpful.
References
  1. ERICKSON SK. Nonalcoholic fatty liver disease J Lipid Res [online] 2009 Apr, 50(Suppl):S412-S416 [viewed 17 May 2014] Available from: doi:10.1194/jlr.R800089-JLR200
  2. MARRERO JA, FONTANA RJ, SU GL, CONJEEVARAM HS, EMICK DM, LOK AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology [online] 2002 Dec, 36(6):1349-54 [viewed 17 May 2014] Available from: doi:10.1053/jhep.2002.36939
  3. EL-SERAG HASHEM B.. Hepatocellular Carcinoma. N Engl J Med [online] 2011 September, 365(12):1118-1127 [viewed 16 May 2014] Available from: doi:10.1056/NEJMra1001683
  4. FIELDING L. Current Imaging Strategies of Primary and Secondary Neoplasms of the Liver Semin Intervent Radiol [online] 2006 Mar, 23(1):3-12 [viewed 16 May 2014] Available from: doi:10.1055/s-2006-939836
  5. OLIVER JH 3RD, BARON RL, FEDERLE MP, ROCKETTE HE JR. Detecting hepatocellular carcinoma: value of unenhanced or arterial phase CT imaging or both used in conjunction with conventional portal venous phase contrast-enhanced CT imaging. AJR Am J Roentgenol [online] 1996 Jul, 167(1):71-7 [viewed 16 May 2014] Available from: doi:10.2214/ajr.167.1.8659425

Investigations - Screening/Staging

Fact Explanation
Liver biopsy Histological examination provides grading of the NAFLD according to the degree of steatosis, lobular inflammation and ballooning. [2]
Hepatic transaminases ALT/AST ratio of greater than 1 is suggestive of more severe fibrosis.[1]
Ultrasound scan of the abdomen Ultrasound scan is operator dependent but useful in screening NAFLD. [3]
References
  1. ANGULO P, KEACH JC, BATTS KP, LINDOR KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology [online] 1999 Dec, 30(6):1356-62 [viewed 17 May 2014] Available from: doi:10.1002/hep.510300604
  2. KLEINER DE, BRUNT EM, VAN NATTA M, BEHLING C, CONTOS MJ, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology [online] 2005 Jun, 41(6):1313-21 [viewed 17 May 2014] Available from: doi:10.1002/hep.20701
  3. TOLMAN KG, DALPIAZ AS. Treatment of non-alcoholic fatty liver disease Ther Clin Risk Manag [online] 2007 Dec, 3(6):1153-1163 [viewed 17 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387293

Management - General Measures

Fact Explanation
Health education Patients with obesity or overweight should be educated to lose weight and maintain normal BMI with regular exercise and healthy dietary practices. [4] However low fat diet and skipping meals should be avoided. [6] Alcohol consumption should be stopped or at least cut down to safe limits. Patients with NAFLD are at risk of cardiovascular complications. [1]
Treatment of associated co-morbidities Patients with metabolic syndrome or type 2 diabetes mellitus are also at risk of NAFLD. They should be educated and encouraged to adhere to healthy dietary practices and life styles. Dyslipidemia, diabetes mellitus and metabolic syndrome should be treated with lipid lowering drugs and hypoglycemic drugs respectively. [5]
Management of HCC If detected early surgical resection or liver transplantation can be done with curative intent. [2,3] Trans arterial chemoembolization (TACE), radiofrequency ablation, percutaneous ethanol injection, cryosurgery, microwave coagulation therapy, yttrium-90 microsphere radio-embolization and chemotherapy are used for palliation. [3]
References
  1. ERICKSON SK. Nonalcoholic fatty liver disease J Lipid Res [online] 2009 Apr, 50(Suppl):S412-S416 [viewed 17 May 2014] Available from: doi:10.1194/jlr.R800089-JLR200
  2. FIELDING L. Current Imaging Strategies of Primary and Secondary Neoplasms of the Liver Semin Intervent Radiol [online] 2006 Mar, 23(1):3-12 [viewed 16 May 2014] Available from: doi:10.1055/s-2006-939836
  3. JELIC S., SOTIROPOULOS G. C.. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology [online] December, 21(Supplement 5):v59-v64 [viewed 16 May 2014] Available from: doi:10.1093/annonc/mdq166
  4. HUANG MA, GREENSON JK, CHAO C, ANDERSON L, PETERMAN D, JACOBSON J, EMICK D, LOK AS, CONJEEVARAM HS. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol [online] 2005 May, 100(5):1072-81 [viewed 17 May 2014] Available from: doi:10.1111/j.1572-0241.2005.41334.x
  5. TOLMAN KG, DALPIAZ AS. Treatment of non-alcoholic fatty liver disease Ther Clin Risk Manag [online] 2007 Dec, 3(6):1153-1163 [viewed 17 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387293
  6. KANG H, GREENSON JK, OMO JT, CHAO C, PETERMAN D, ANDERSON L, FOESS-WOOD L, SHERBONDY MA, CONJEEVARAM HS. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol [online] 2006 Oct, 101(10):2247-53 [viewed 17 May 2014] Available from: doi:10.1111/j.1572-0241.2006.00719.x

Management - Specific Treatments

Fact Explanation
Antioxidants [1] Antioxidants are used because of their inhibitory action on hepatic stellate cells. Vitamin E is currently used in treatment. [1]
Bariatric surgery This is the only available treatment option to change the natural progression of the disease. [1]
Orlistat This is a lipase inhibitor and inhibit the dietary fat absorption. [1]
Sibutramine Supresses the appetite and aid in weight loss. [1]
Thiazolidinedione Increases insulin sensitivity. [1]
Metformin [1] A biguanide which is an oral hypoglycemic drug. Metformin helps to overcome the insulin resistance and suppress lipogenic enzymes. [1]
Lipid lowering drugs Statins (atorvastatin, pravastatin, and rosuvastatin) are currently used to treat NAFLD. [2]
Ursodeoxycholic acid This is an anti-apoptotic drug with cyto-protective, immune-modulating, anti-inflammatory actions. [3]
References
  1. TOLMAN KG, DALPIAZ AS. Treatment of non-alcoholic fatty liver disease Ther Clin Risk Manag [online] 2007 Dec, 3(6):1153-1163 [viewed 17 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387293
  2. KIYICI M, GULTEN M, GUREL S, NAK SG, DOLAR E, SAVCI G, ADIM SB, YERCI O, MEMIK F. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol [online] 2003 Dec, 17(12):713-8 [viewed 18 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/14679419
  3. LAURIN J, LINDOR KD, CRIPPIN JS, GOSSARD A, GORES GJ, LUDWIG J, RAKELA J, MCGILL DB. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology [online] 1996 Jun, 23(6):1464-7 [viewed 18 May 2014] Available from: doi:10.1002/hep.510230624