Non-alcoholic fatty liver disease differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Overview

NAFLD must be differentiated from other diseases that cause jaundice and abdominal pain which include Wilson's disease, hemochromatosis, alcoholic hepatitis and cholestatic jaundice.

Differential Diagnosis

NAFLD must be differentiated from other diseases that cause hepatomegaly, jaundice, cirrhosis and ascites.

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever RUQ Pain Pruritis AST ALT ALK BLR Indirect BLR Direct Viral serology Jaundice Hepatocellular Jaundice Hemochromatosis + - -/+ - ↑ ↑ ↑/N ↑/N N - Ferritin ↑ Liver biopsy Wilson's disease + - -/+ - ↑ ↑ N ↑/N N - Serum cerulloplasmin ↑ Liver biopsy Alcoholic hepatitis - -/+ -/+ - ↑↑ ↑ N ↑/N N - - - Cirrhosis -/+ -/+ -/+ - ↑ ↑ ↑/N ↑/N ↑/N -/+ Low platate Small liver on ultrasond Cholestatic Jaundice Common bile duct stone -/+ - + + N N ↑ N ↑ - Dilated ducts on sono CT/ERCP Hepatitis A cholestatic type - -/+ + + N N ↑ N ↑ + HAV- AB Abdominal ultrasound EBV / CMV hepatitis - -/+ + + N N ↑ N ↑ + Positive serology Primary biliary cirrhosis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - AMA positive Liver biopsy Primary sclerosing cholangitis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - Beading on MRCP Liver biopsy Pancreatic carcinoma + - -/+ - N/↑ N/↑ ↑ N ↑ - Mass on ultrasond CT scan for diagnosis

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease Clinical manifestations Diagnosis Comments Symptoms Signs Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Acute suppurative cholangitis RUQ + + + + − − − − + + + N Abnormal LFT WBC >10,000 Ultrasound shows biliary dilatation/stents/tumor Septic shock occurs with features of SIRS Acute cholangitis RUQ + − − + − − − − − − − N Abnormal LFT Ultrasound shows biliary dilatation/stents/tumor Biliary drainage (ERCP) + IV antibiotics Acute cholecystitis RUQ + − + + − − − − − − − Hypoactive Hyperbilirubinemia Leukocytosis Ultrasound shows: Gallstone Inflammation Murphy’s sign Acute pancreatitis Epigastric + − + ± − − − − ± − − N Increased amylase / lipase Ultrasound shows evidence of inflammation CT scan shows severity of pancreatitis Pain radiation to back Chronic pancreatitis Epigastric − − ± ± − + + − − − − N Increased amylase / lipase Increased stool fat content Pancreatic function test CT scan Calcification Pseudocyst Dilation of main pancreatic duct Predisposes to pancreatic cancer Pancreatic carcinoma Epigastric − − + + − + + − − − − N ↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9  MDCT with  PET/CT MRI Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Primary biliary cirrhosis RUQ/Epigastric − − − + − − − − − − − N Increased AMA level, abnormal LFTs ERCP Pruritis Primary sclerosing cholangitis RUQ + − − + − − − − − − − N Increased liver enzymes Increased IgM, IgG4 Anti-neutrophil cytoplasmic antibody (p-ANCA) Anti-nuclear antibody (ANA) Anti-smooth muscle antibody (Anti-Sm) Anti-endothelial antibody Anti-cardiolipin antibody ERCP and MRCP shows Multiple segmental strictures Mural irregularities Biliary dilatation and diverticula Distortion of biliary tree The risk of cholangiocarcinoma in patients with primary sclerosing cholangitis is 400 times higher than the risk in the general population. Cholelithiasis RUQ/Epigastric ± − ± ± − − − − − − − Normal to hyperactive for dislodged stone Leukocytosis Ultrasound shows gallstone Fatty food intolerance Gastrointestinal perforation Diffuse + ± - ± − − − + + + ± Hyperactive/hypoactive WBC> 10,000 Air under diaphragm in upright CXR Hamman's sign Inflammatory bowel disease Diffuse ± − − ± − + + + − − − Normal or hyperactive Anti-neutrophil cytoplasmic antibody (P-ANCA) in Ulcerative colitis Anti saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease String sign on abdominal x-ray in Crohn's disease Extra intestinal findings: Uveitis Arthritis Whipple's disease Diffuse ± − − ± − + + − ± − − N Thrombocytopenia Hypoalbuminemia Small intestinal biopsy for Tropheryma whipplei Endoscopy is used to confirm diagnosis. Images used to find complications Chest and joint x-ray CT MRI Echocardiography Extra intestinal findings: Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Arthritis Ascites Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Viral hepatitis RUQ + − + + − Positive in Hep A and E + − Positive in fulminant hepatitis Positive in acute + N Abnormal LFTs Viral serology US Hep A and E have fecal-oral route of transmission Hep B and C transmits via blood transfusion and sexual contact. Liver abscess RUQ + + + + − ± + − + + ± Normal or hypoactive CBC Blood cultures Abnormal liver function tests US CT Hepatocellular carcinoma/Metastasis RUQ + − − + − − + − − − − Normal Hyperactive if obstruction present High levels of AFP in serum Abnormal liver function tests US CT Liver biopsy Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Budd-Chiari syndrome RUQ ± − − ± − − − Positive in liver failure leading to varices − − − N Elevated serum aspartate aminotransferase and alanine aminotransferase levels may be more than five times the upper limit of the normal range. Elevated serum alkaline phosphatase and bilirubin levels, decreased serum albumin level. Findings on CT scan suggestive of Budd-Chiari syndrome include: Early enhancement of the caudate lobe and central liver around the inferior vena cava Delayed enhancement of the peripheral liver with accompanying central low density (flip-flop appearance) Peripheral zones of the liver show reversed portal venous blood flow In the chronic phase, there is caudate lobe enlargement and atrophy of the peripheral liver in affected areas Ascitic fluid examination shows: Total protein more than 2.5 g per deciliter White blood cells are usually less than 500/μL. Cirrhosis RUQ − − − + − − + + + − − N Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia US Nodular, shrunken liver Ascites Stigmata of liver disease Cruveilhier- Baumgarten murmur Spontaneous bacterial peritonitis Diffuse + − − Positive in cirrhotic patients − + − − ± + + Hypoactive Ascitic fluid PMN>250 cells/mm³ Culture: Positive for single organism Ultrasound for evaluation of liver cirrhosis Biliary colic RUQ − − + + − − − − − − − N ↑ bilirubin and alkaline phosphatase Ultrasound