Cirrhosis differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]

Overview

Cirrhosis may present in a similar way to some other diseases. History, physical examination, and diagnostic testing may help in differentiating cirrhosis from other diseases such as malignancy, constrictive pericarditis, Budd-Chiari syndrome, portal vein thrombosis and splenic vein thrombosis.

Differentiating Cirrhosis From Other Diseases

Differential diagnosis of jaundice

Differential diagnosis of jaundice are enlisted in the table below:

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever Right upper quadrant (RUQ) Pain Pruritis Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) ALK Bilirubin (Indirect) Bilirubin (Direct) Viral serology Jaundice Hepatocellular Jaundice Liver infiltration: Hemochromatosis, amyloidosis + - -/+ - ↑ ↑ ↑/N ↑/N N - Ferritin ↑ in hemochromatosis Liver biopsy Wilson's disease + - -/+ - ↑ ↑ N ↑/N N - Serum ceruloplasmin ↑ 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 platelet count Small liver on ultrasound Nonalcoholic steatohepatitis -/+ - - - ↑ ↑ N ↑/N N - High lipids Liver biopsy Ischemic hepatopathy -/+ - -/+ - ↑ ↑ N ↑/N N - Cardiovascular risk factors Clinical setting Cholestatic Jaundice Common bile duct stone -/+ - + + N N ↑ N ↑ - Dilated ducts on sonography CT scan/ERCP Hepatitis A (cholestatic type) - -/+ + + N N ↑ N ↑ + Anti-HAV antibody Abdominal ultrasound EBV / CMV hepatitis - -/+ + + N N ↑ N ↑ + Positive serology - Primary biliary cirrhosis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - Antimitochondrial antibody (AMA) positive Liver biopsy Primary sclerosing cholangitis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - Positive autoantibodies (p-ANCA) Beading on MRCP, Liver biopsy Sickle cell disease + - - +/- N/↑ N/↑ ↑ N ↑ - Genetic testing Pancreatic carcinoma + - -/+ -/+ N/↑ N/↑ ↑ N ↑ - - CT scan for diagnosis AIDS cholangiopathy - - -/+ -/+ N/↑ N/↑ ↑ N ↑ - Positive HIV Sonography or ERCP for diagnosis Parasite induces cholestasis - - -/+ -/+ N/↑ N/↑ ↑ N ↑ - Antibodies or parasite serology Sonography or ERCP for diagnosis Intrahepatic cholestasis of pregnancy -/+ - -/+ + ↑ ↑ ↑ N ↑ - Low platelets, Negative viral serology Diagnosed clinically Isolated Jaundice Crigler-Najjar type 2 + - - - N N N ↑ ↑ - Genetic testing Gilbert syndrome + - - - 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 Hereditary spherocytosis + - -/+ - N N N ↑ N - Genetic testing Osmotic fragility Glucose 6 phosphate dehydrogenase (G6PD) deficiency + - - - N N N ↑ N - Genetic testing Thalassemia + - - - N N N ↑ N - Genetic testing Paroxysmal nocturnal hemoglobinuria (PNH) - - - - N N N ↑ N - Flow cytometery Immune hemolysis - -/+ - - N N N ↑ N - Autoantibodies Hematoma - -/+ - - N N N ↑ N - Anemia Trauma or surgery in history

Differentiating cirrhosis from other diseases based on serum-ascites albumin gradient (SAAG)

• Ascites may be caused by portal hypertension due to cirrhosis of liver or due to other causes such as malignancy. Ascitic fluid analysis should be done to broadly categorize the cause of ascites.

• Ascites is broadly classified as two types based on the serum-ascites albumin gradient (SAAG):
  • Transudate - SAAG > 1.1 g/dL (indicative of ascites due to portal hypertension)
  • Exudate - SAAG < 1.1 g/dL (indicative of ascites due to other etiologies)

Cirrhosis must be differentiated from other causes of abnormal liver function tests, altered liver architecture and size:

Condition	Differentiating signs and symptoms	Differentiating Tests
Cirrhosis	Abdominal pain and bloating Menstrual irregularities Symptoms of hypogonadism: Impotence Infertility Testicular atrophy Loss of libido Easy bruisability Decompensated cirrhosis may present with Jaundice Increase in abdominal girth due to ascites Pruritus Signs of upper gastrointestinal bleeding: Hematemesis Hematochezia Melena Symptoms due to hepatic encephalopathy: Altered mental status Confusion Sleep disturbances	Ultrasound findings in cirrhosis are as follows: Changes in liver contour: shrunken, irregular appearance Non homogeneous appearance of the hepatic tissue Increased surface nodularity Increase in echogenecity from focal fatty infiltration Atrophy of the right lobe and hypertrophy of the caudate or left lobe Splenomegaly Ascites Varices Hepatic or portal vein thrombosis Abdominal MRI may also be helpful in the diagnosis of portal hypertension. Findings on MRI suggestive of cirrhosis with portal hypertension include: Cirrhotic liver, as shrinkage and atrophy in liver Re-canalized umbilical vein--pathognomonic Dilated portal vein and/or splanchnic veins Esophageal varices Collaterals in any abdominal organ Splenomegaly Ascites Transient elastography and the Acoustic Radiation Force Impulse (ARFI) technique are well-established methods for the staging of fibrosis in various liver diseases:   The FibroScan (transient elastography) uses elastic waves to determine liver stiffness which theoretically may be converted into a liver score. The FibroScan produces an ultrasound image of the liver (from 20-80mm) along with a pressure reading (in kPa). Transient elastography is much faster than a biopsy (usually lasts 2.5-5 minutes) and is completely painless. Findings on transient elastography may show reasonable correlation with the severity of cirrhosis: Increasing scarring of the liver is associated with increasing "stiffness" of the tissue.
Constrictive pericarditis	Increased jugular venous pressure Atrial fibrillation Tachycardia Faint heart sounds with a third heart sound (ventricular knock)	EKG will show: Tachycardia Atrial fibrillation Low-voltage QRS complexes T wave abnormalities Doppler ultrasound shows ventricular filling abnormalities
Budd-Chiari Syndrome	Abdominal pain Diarrhea Ascites	Doppler ultrasound and CT of the abdomen shows absence of the hepatic vein filling Abdominal CT scan will show a rapid clearing of the caudate lobe of the liver
Splenic vein thrombosis	Signs and symptoms of: Upper abdominal pain radiating to the back Vomiting Hypoactive bowel sounds Fever Shock Cullen's sign Grey-Turner's sign	Ultrasound of the abdomen and CT scan will show evidence of a splenic vein thrombosis Normal hepatic venous pressure gradient is present
Portal vein thrombosis	Symptoms depend on the underlying cause: If pancreatitis is present, the patient may develop: Upper abdominal pain radiating to the back Vomiting Hypoactive bowel sounds fever shock Cullen's sign Grey-Turner's sign If the cause is ascending cholangitis, symptoms include: Fever Rigors Right upper quadrant pain Dark urine Pale stools If abdominal sepsis is the cause, symptoms include: Fever Abdominal pain Signs of peritonitis	Doppler ultrasound and abdominal CT scan show a portal vein filling defect and absence of flow in the portal vein. MR or direct angiography show a normal hepatic venous pressure gradient.
Schistosomiasis	Patients may have a history of travel to endemic areas Constitutional symptoms such as Malaise Rigors Anorexia Weight loss Vomiting Diarrhea Headache Muscular aches Weakness Abdominal pain Urticaria Fever Lymphadenopathy	MR or direct angiography shows a normal hepatic venous pressure gradient
Sarcoidosis	Dry cough with dyspnea Anterior or posterior uveitis Dry eyes glaucoma Skin findings may include: Maculopapular lesions on the face, back, arms and legs Erythema nodosum on the legs	Chest x ray may show: Hilar lymphadenopathy Upper lobe fibrosis Diffuse reticulonodular shadowing Liver biopsy shows non-necrotizing, non-caseating granulomas
Inferior vena cava obstruction	Signs and symptoms of renal cell carcinoma: Hematuria Flank pain Flank or abdominal mass Weight loss Hypertension	Ultrasound of the abdomen shows evidence of inferior vena cava obstruction
Nodular regenerative hyperplasia	None	Liver biopsy shows small regenerative nodules with little or no fibrosis on reticulin staining
Idiopathic portal hypertension (hepatoportal sclerosis)	None	Liver biopsy shows no evidence of cirrhosis
Vitamin A intoxication, arsenic, and vinyl chloride toxicity	None	History generally reveals exposure

Differentiating Cirrhosis from other causes of jaundice and abdominal pain

Cirrhosis must be differentiated from other diseases that cause jaundice, abdominal pain, weight loss, and fever such as Gallbladder cancer, hepatocellular carcinoma, pancreatic cancer, cholecystitis, choledochitis and liver fluke infections.

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
Cholangiocarcinoma	RUQ	+	−	+	+	−	−	+	−	−	−	+	Normal	Elevated CA 19-9 Increased amylase / lipase Increased stool fat content	Contrast-enhanced ultrasound CT scan Calcification Pseudocyst Dilation of main pancreatic duct MRI	Predisposes to pancreatic cancer
Hepatocellular carcinoma/Metastasis	RUQ	+	−	+	+	+	+	+	+	+	−	+	Normal Hyperactive if obstruction present	High levels of AFP in serum Abnormal liver function tests Thrombocytopenia	US CT MRI Liver biopsy	Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis
Pancreatic carcinoma	MidEpigastric	−	−	+	+	+	−	+	−	−	−	+	Normal	↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9	MDCT with PET/CT MRI EUS	Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis
Focal nodular hyperplasia	Diffuse	±	−	−	±	−	−	+	+	−	−	−	Normal	Normal Liver function tests Normal AFP Minor elevations of Aspartate Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transpeptidase	Us Multiphasic helical CT scan	Open biopsy if diagnosis can not be established
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
Gallbladder cancer	Midepigastric	−	−	+	+	−	+	+	−	−	−	−	Normal	↑ Alkaline phosphatase ↑ CA 19-9	US CT MRI
Liver hemangioma	Intermittent RUQ	−	−	+	+	−	−	−	−	−	−	−	Normal	Abnormal LFTs	US Single-photon emission computerized tomography(SPECT) MRI	US will reveal hypoechoic lesions
Liver abscess	RUQ	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Abnormal liver function tests	US CT
Cirrhosis	RUQ+Bloating	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular, shrunken liver Ascites	Stigmata of liver disease Cruveilhier- Baumgarten murmur
Inflammatory lesions	RUQ	±	−	+	+	−	−	−	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular,shrunken or coarse liver	Stigmata of liver disease

References