Primary sclerosing cholangitis differential diagnosis

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

Overview

Primary sclerosing cholangitis must be differentiated from causes of secondary sclerosing cholangitis.

Differentiating Primary sclerosing cholangitis from other Diseases

Primary sclerosing cholangitis must be differentiated from causes of secondary sclerosing cholangitis. These include:

• Abdominal trauma
• AIDS-related cholangiopathy
• Amyloidosis
• Chronic bacterial cholangitis
• GVHD
• Hepatic inflammatory pseudo tumor
• Histiocytosis X
• Iatrogenic biliary strictures, due to surgery or ERCP
• IgG4-associated cholangitis
• Infectious or ischemic cholangiopathy
• Cholangiocarcinoma
• Choledocholithiasis
• Diffuse intra-hepatic metastases
• Eosinophilic cholangitis
• Intra-arterial chemotherapy
• Mast cell cholangiopathy
• Portal hypertensive biliopathy
• Recurrent pancreatitis
• Recurrent pyogenic cholangitis
• Sarcoidosis

Primary sclerosing cholangitis must be differentiated from other causes of jaundice:

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 Viral hepatitis - -/+ - - ↑ ↑ N ↑/N N + Specific viral antibody for each type - Alcoholic hepatitis - -/+ -/+ - ↑↑ ↑ N ↑/N N - - - Drug induced hepatitis - -/+ - - ↑ ↑ N ↑/N N - - - Autoimmune hepatitis -/+ - - -/+ ↑ ↑ N ↑/N N - Anti-LKM antibody Liver biopsy 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 Isolated Jaundice Crigler-Najjar type 2 + - - - N N N ↑ ↑ - Genetic testing Gilbert + - - - N N N ↑ ↑ - Genetic testing Rotor syndrome + - - - N N N N ↑ - Genetic testing Liver biopsy Dubin-Johnson syndrome + - - - N N N N ↑ - Genetic testing Liver biopsy Hereditory spherocytosis + - -/+ - N N N ↑ N - Genetic testing Osmotic fragility G6PD deficiency + - - - N N N ↑ N - Genetic testing Thalassemia + - - - N N N ↑ N - Genetic testing Sickle cell disease + - - - N N N ↑ N - Genetic testing Paroxismal nocturnal hemoglobinoria - - - - N N N ↑ N - Flocytometery Immune hemolysis - -/+ - - N N N ↑ N - Autoantibodies Hematoma - -/+ - - N N N ↑ N - Anemia Truma or surgery in history

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

Primary sclerosing cholangitis must be differentiated from other abdominal pain causes:

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 Peptic ulcer disease Diffuse ± − + − − − + Gastric ulcer- melena and hematemesis Duodenal ulcer- melena and hematochezia Positive if perforated Positive if perforated Positive if perforated N Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl Air under diaphragm in upright CXR Upper GI endoscopy for diagnosis 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 Acute appendicitis Starts in epigastrium, migrates to RLQ + Positive in pyogenic appendicitis + − − ± − − Positive in perforated appendicitis + + Hypoactive Leukocytosis Ct scan Ultrasound Positive Rovsing sign Positive Obturator sign Positive Iliopsoas sign Acute diverticulitis LLQ + ± + − + ± − + Positive in perforated diverticulitis + + Hypoactive Leukocytosis CT scan Ultrasound History of constipation 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 Irritable bowel syndrome Diffuse − − − − ± ± + − − − − N Normal Normal Symptomatic treatment High dietary fiber Osmotic laxatives Antispasmodic drugs 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 Colon carcinoma Diffuse/localized − − − − ± ± + + ± − − Normal or hyperactive if obstruction present CBC Carcinoembryonic antigen (CEA) Colonoscopy Flexible sigmoidoscopy Barium enema CT colonography  PILLCAM 2: A colon capsule for CRC screening may be used in patients with an incomplete colonoscopy who lacks obstruction 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 Hemochromatosis RUQ − − − − − − − Positive in cirrhotic patients − − − N >60% TS >240 μg/L SF Raised LFT Hyperglycemia Ultrasound shows evidence of cirrhosis Extra intestinal findings: Hyperpigmentation Diabetes mellitus Arthralgia Impotence in males Cardiomyopathy Atherosclerosis Hypopituitarism Hypothyroidism Extrahepatic cancer Prone to specific infections Cirrhosis RUQ − − − + − − + + + − − N Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia US Nodular, shrunken liver Ascites Stigmata of liver disease Cruveilhier- Baumgarten murmur 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 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