History

Fact Explanation
Asymptomatic Most affected patients are asymptomatic. Hepatic steatosis develops in the absence of alcohol abuse. [5]
Presence of risk factors Obesity, hypertension, diabetes mellitus, metabolic syndrome, polycystic ovarian syndrome and dyslipidemia are recognized risk factors for the development of NASH. Positive family history of hypercholesterolemia should also be looked for. Females in reproductive age group should be asked for menstrual irregularities, recent weight gain and glucose intolerance. [3,4]
History of non-alcoholic fatty liver disease (NAFLD) NAFLD occurs due to excessive accumulation of fat in the hepatocytes. If not reversed it can progress to NASH. [3]
Symptoms of cirrhosis If patients are not detected early, NASH can progress to permanent liver damage and cirrhosis. Hematemesis, melena, symptoms of hepatic encephalopathy (altered consciousness, reversed sleep-wake pattern, disorientation, coma). Some patients may develop hepatocellular carcinoma due to longstanding cirrhosis. [1,2,4]
Symptoms of hepatoellular carcinoma (HCC) HCC is a known complication of long standing cirrhosis due to NASH. Patients can present with abdominal pain due to stretching of the liver capsule. Loss of weight and loss of appetite are other possible presentations of HCC. [6]
References
  1. SCHUPPAN DETLEF, AFDHAL NEZAM H. Liver cirrhosis. The Lancet [online] 2008 March, 371(9615):838-851 [viewed 03 August 2014] Available from: doi:10.1016/S0140-6736(08)60383-9
  2. AL-OSAIMI ABDULLAHM. S., BLEIBEL WISSAM. Hepatic encephalopathy. Saudi J Gastroenterol [online] 2012 December [viewed 03 August 2014] Available from: doi:10.4103/1319-3767.101123
  3. KIM YS, JUNG ES, HUR W, BAE SH, CHOI JY, SONG MJ, KIM CW, JO SH, LEE CD, LEE YS, CHOI SW, YANG JM, JANG JW, KIM SG, JUNG SW, KIM HK, CHAE HB, YOON SK. Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease Clin Mol Hepatol [online] 2013 Jun, 19(2):120-130 [viewed 03 August 2014] Available from: doi:10.3350/cmh.2013.19.2.120
  4. SUMIDA Y, NAKAJIMA A, ITOH Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis World J Gastroenterol [online] 2014 Jan 14, 20(2):475-485 [viewed 03 August 2014] Available from: doi:10.3748/wjg.v20.i2.475
  5. MEDINA J., FERNANDEZ-SALAZAR L. I., GARCIA-BUEY L., MORENO-OTERO R.. Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis. Diabetes Care [online] 2004 August, 27(8):2057-2066 [viewed 04 August 2014] Available from: doi:10.2337/diacare.27.8.2057
  6. SHRAGER BRIAN, JIBARA GHALIB A., TABRIZIAN PARISSA, ROAYAIE SASAN, WARD STEPHEN C.. Resection of Nonalcoholic Steatohepatitis-Associated Hepatocellular Carcinoma: A Western Experience. International Journal of Surgical Oncology [online] 2012 December, 2012:1-7 [viewed 04 August 2014] Available from: doi:10.1155/2012/915128

Examination

Fact Explanation
BMI Most of the affected patients are obese and tend to have increased waist circumference. In normal population BMI varies from 18.50kg/m2 to 24.99kg/m2. BMI of more than 25kg/m2 is considered overweight and more than 30kg/m2 are considered obese. [1,2]
Waist to hip circumference ratio If the ratio of waist circumference (narrowest circumference of the waist) and hip circumference (widest circumference of the hip) is more than 0.85 in females and more than 0.90 in males it indicated abdominal obesity.
Blood pressure Patients with NASH can have comorbid hypertension as an association.
Abdominal examination Hepatomegaly can be detected in some patients with NASH. If the patient has developed cirrhosis liver will be shrunken and nodular with irregular margins. Liver mass with audible hepatic bruit can be detected if hepatocellular carcinoma is present. Splenomegaly can also be detected in the presence of portal hypertension. [3]
Stigmata of chronic liver disease Patients who have developed cirrhosis can have peripheral stigmata of chronic liver disease.
Stigmata of hypercholestrolemia Xantholesma, xanthomata and corneal arcus can be seen in patients with hypercholestrolemia.
References
  1. KIM YS, JUNG ES, HUR W, BAE SH, CHOI JY, SONG MJ, KIM CW, JO SH, LEE CD, LEE YS, CHOI SW, YANG JM, JANG JW, KIM SG, JUNG SW, KIM HK, CHAE HB, YOON SK. Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease Clin Mol Hepatol [online] 2013 Jun, 19(2):120-130 [viewed 03 August 2014] Available from: doi:10.3350/cmh.2013.19.2.120
  2. SUMIDA Y, NAKAJIMA A, ITOH Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis World J Gastroenterol [online] 2014 Jan 14, 20(2):475-485 [viewed 03 August 2014] Available from: doi:10.3748/wjg.v20.i2.475
  3. MALNICK S.D.H., BEERGABEL M., KNOBLER H.. Non-alcoholic fatty liver: a common manifestation of a metabolic disorder. QJM [online] December, 96(10):699-709 [viewed 04 August 2014] Available from: doi:10.1093/qjmed/hcg120

Differential Diagnoses

Fact Explanation
Nonalcoholic fatty liver disease (NAFLD) NAFLD is hepatic steatosis which is not associated with alcohol abuse. NAFLD can progress to NASH and finally resulting cirrhosis. [1]
Autoimmune hepatitis Circulating autoantibodies causes chronic inflammation damaging the hepatocytes. Autoimmune hepatitis can progress to cirrhosis. [3]
Acute hepatitis Acute hepatitis B and C can be sometimes asymptomatic or present with jaundice. Both conditions cause elevation of hepatic transaminases and may progress to cirrhosis.
Primary biliary cirrhosis Primary biliary cirrhosis is another cause of elevated hepatic transaminases, deranged liver function and cirrhosis. [2]
Alcoholic hepatitis Alcoholic hepatitis causes symptoms and signs of liver dysfunction. Liver transaminases are elevated in both conditions. History of alcohol abuse is more favor of alcoholic liver disease rather NASH.
Wilson disease Wilson disease is an inherited disorder of copper metabolism. Patients can be asymptomatic or present with either hepatic or neuropsychiatric manifestations (chorea, parkinsonism). [4]
References
  1. ERICKSON SK. Nonalcoholic fatty liver disease J Lipid Res [online] 2009 Apr, 50(Suppl):S412-S416 [viewed 04 August 2014] Available from: doi:10.1194/jlr.R800089-JLR200
  2. NGUYEN DL, JURAN BD, LAZARIDIS KN. Primary Biliary Cirrhosis Best Pract Res Clin Gastroenterol [online] 2010 Oct, 24(5):647-654 [viewed 04 August 2014] Available from: doi:10.1016/j.bpg.2010.07.006
  3. MAKOL ASHIMA, WATT KYMBERLY D., CHOWDHARY VAIDEHI R.. Autoimmune Hepatitis: A Review of Current Diagnosis and Treatment. Hepatitis Research and Treatment [online] 2011 December, 2011:1-11 [viewed 04 August 2014] Available from: doi:10.1155/2011/390916
  4. DAS SHYAMAL K, RAY KUNAL. Wilson's disease: an update. Nat Clin Pract Neurol [online] 2006 September, 2(9):482-493 [viewed 04 August 2014] Available from: doi:10.1038/ncpneuro0291

Investigations - for Diagnosis

Fact Explanation
Hepatic transaminases Alanine transaminase (ALT) and aspartate transaminase (AST) can be either elevated or normal in NASH. However this is not a specific finding because elevated transaminases can be seen in many disease conditions. [1,2]
Alkaline phosphatase Alkaline phosphatase levels are elevated.
Ultrasound scan of the abdomen This is noninvasive and relatively cheap investigation useful in diagnosis of NASH. Ultrasound scan shows a "bright" liver with increased echogenicity. Hepatic vasculature is blurred in NASH.
CT CT scan can also be used to diagnose NASH by detecting steatosis and hepatomegaly. However when compared to ultrasound scan, CT scan carries increased risk of radiation.
MRI MRI is useful in diagnosing NASH. MRI scan and CT scan show similar findings.
Magnetic resonance spectroscopy Although not widely used magnetic resonance spectroscopy is considered the most accurate imaging modality to detect fatty infiltration of hepatocytes. [2]
Liver biopsy Liver biopsy is considered the gold standard in diagnosing NASH. Hepatocytes show steatosis, liver cell injury, ballooning degeneration, increased apoptosis and inflammation. Mallory-Denk bodies can also be seen in some patients. These changes are marked in zone 3. [1,2,3]
Serum ferritin Serum ferritin levels are elevated due to inflammation of the liver in NASH. [2]
Serum cytokeratin-18 (CK18) fragments This is considered a novel biomarker of hepatic steatosis and fibrosis. [2]
References
  1. KIM YS, JUNG ES, HUR W, BAE SH, CHOI JY, SONG MJ, KIM CW, JO SH, LEE CD, LEE YS, CHOI SW, YANG JM, JANG JW, KIM SG, JUNG SW, KIM HK, CHAE HB, YOON SK. Noninvasive predictors of nonalcoholic steatohepatitis in Korean patients with histologically proven nonalcoholic fatty liver disease Clin Mol Hepatol [online] 2013 Jun, 19(2):120-130 [viewed 03 August 2014] Available from: doi:10.3350/cmh.2013.19.2.120
  2. SUMIDA Y, NAKAJIMA A, ITOH Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis World J Gastroenterol [online] 2014 Jan 14, 20(2):475-485 [viewed 03 August 2014] Available from: doi:10.3748/wjg.v20.i2.475
  3. BAYARD M, HOLT J, BOROUGHS E. Nonalcoholic fatty liver disease. Am Fam Physician [online] 2006 Jun 1, 73(11):1961-8 [viewed 04 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16770927

Investigations - Fitness for Management

Fact Explanation
Fasting blood sugar Patients with metabolic syndrome can have diabetes and high fasting blood sugar levels. [1]
Glucose tolerance test Patients with metabolic syndrome can have impaired glucose tolerance test. [1]
Lipid profile Elevated total cholesterol levels, triglycerides and low-density lipoprotein (LDL) levels with low high-density lipoprotein (HDL) can be seen in some patients with metabolic syndrome. [1]
ECG Patients with metabolic syndrome can have ischemic heart diseases. ECG can show any acute myocardial ischemia and previous myocardial infarction (pathological Q waves).
References
  1. OPIE L. H.. Metabolic Syndrome. Circulation [online] 2007 January, 115(3):e32-e35 [viewed 05 August 2014] Available from: doi:10.1161/​CIRCULATIONAHA.106.671057

Investigations - Followup

Fact Explanation
Serum cholesterol levels Patients with obesity and or metabolic syndrome are at risk of hypercholesterolemia. Evaluation of lipid profile in patients allow early identification and treatment of hypercholesterolemia. Total cholesterol levels of less than 160mg/dl is desirable. Level between 160 to 199mg/dl is desirable, 200 to 239mg/dl is borderline risk and if LDL is more than 240mg/dl it carries a significant risk of ischemic heart disease. [1]
LDL choleserol levels Serum LDL cholesterol level of less than 100mg/dl is considered optimal. Levels between 100 to 129mg/dl are considered desirable. If LDL cholesterol level is 130 to 159 patients have borderline risk of developing ischemic heart disease. LDL levels of more than 160mg/dl put the patient at very high risk of developing ischemic heart disease. [1]
HDL cholesterol HDL cholesterol of more than 60mg/dl is cardioprotective. Men should have more than 40 mg/dL HDL and women should have more than 50 mg/dL.
Hepatic transaminases If the disease progresses to cirrhosis hepatic transaminases gradually increase and if it is reversed hepatic transaminases will decline. Assessment of hepatic transaminases should be done regularly to monitor the disease progression.
Ultrasound scan of the abdomen Ultrasound scan of the abdomen is useful to evaluate the disease progression and to identify irreversible liver damage leading to cirrhosis.
Serum alpha-feto protein. (AFP) AFP is a tumor marker. It is combined with the ultrasound assessment for the surveillance of hepatocellular carcinoma. [2]
References
  1. GRUNDY S. M.. Small LDL, Atherogenic Dyslipidemia, and the Metabolic Syndrome. Circulation [online] 1997 January, 95(1):1-4 [viewed 05 August 2014] Available from: doi:10.1161/​01.CIR.95.1.1
  2. SINGAL A., VOLK M. L., WALJEE A., SALGIA R., HIGGINS P., ROGERS M. A. M., MARRERO J. A.. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. [online] 2009 July, 30(1):37-47 [viewed 05 August 2014] Available from: doi:10.1111/j.1365-2036.2009.04014.x

Management - General Measures

Fact Explanation
Health education NASH is potentially reversible disease. Patients should be adhered to healthy dietary practices and regular exercise. Patients with diabetes mellitus should achieve a better blood sugar control. [1]
References
  1. AL-BUSAFI SAID A., BHAT MAMATHA, WONG PHILIP, GHALI PETER, DESCHENES MARC. Antioxidant Therapy in Nonalcoholic Steatohepatitis. Hepatitis Research and Treatment [online] 2012 December, 2012:1-8 [viewed 03 August 2014] Available from: doi:10.1155/2012/947575

Management - Specific Treatments

Fact Explanation
Weight reduction Obese patients with NASH should reduce their weight. If the patients find it difficult to lose weight by dietary modifications and with exercise, drugs can be prescribed to suppress the appetite (orlistat) and to lose weight. Targeted weight loss should be about 0.45 to 0.90 kg a week. [1,2]
Oral hypoglycemic drugs Even in the absence of diabetes mellitus, patients with NASH can be prescribed oral hypoglycemic drugs which are proven to reduce elevated hepatic transaminases and hepatic steatosis. Metformin, rosiglitazone and pioglitazone are used in the treatment. [1,2,3]
Vitamin E Patients with NASH can be prescribed vitamin E (1,000 IU per day) which is known to reduce the hepatic fibrosis. Vitamin E is often combined with vitamin C (1,000 mg per day). [1,2]
Betaine Betaine is a nutritional supplement which raises S-adenosylmethionine levels, and reduce hepatic steatosis. [1]
Bariatric surgery Bariatric surgery (reducing the size of the stomach with a gastric band, sleeve gastrectomy or biliopancreatic diversion with duodenal switch) are indicated in patients with NASH and obesity (BMI equal or more than 30kg/m2). These procedures help in loosing weight and proven to reduce steatosis and complications related to metabolic syndrome as well. [4]
References
  1. BAYARD M, HOLT J, BOROUGHS E. Nonalcoholic fatty liver disease. Am Fam Physician [online] 2006 Jun 1, 73(11):1961-8 [viewed 04 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16770927
  2. MEDINA J., FERNANDEZ-SALAZAR L. I., GARCIA-BUEY L., MORENO-OTERO R.. Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis. Diabetes Care [online] 2004 August, 27(8):2057-2066 [viewed 04 August 2014] Available from: doi:10.2337/diacare.27.8.2057
  3. SANYAL ARUN J., CHALASANI NAGA, KOWDLEY KRIS V., MCCULLOUGH ARTHUR, DIEHL ANNA MAE, BASS NATHAN M., NEUSCHWANDER-TETRI BRENT A., LAVINE JOEL E., TONASCIA JAMES, UNALP AYNUR, VAN NATTA MARK, CLARK JEANNE, BRUNT ELIZABETH M., KLEINER DAVID E., HOOFNAGLE JAY H., ROBUCK PATRICIA R.. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med [online] 2010 May, 362(18):1675-1685 [viewed 04 August 2014] Available from: doi:10.1056/NEJMoa0907929
  4. CHAVEZ-TAPIA NC, TELLEZ-AVILA FI, BARRIENTOS-GUTIERREZ T, MENDEZ-SANCHEZ N, LIZARDI-CERVERA J, URIBE M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev [online] 2010 Jan 20:CD007340 [viewed 05 August 2014] Available from: doi:10.1002/14651858.CD007340.pub2