Provide lists of causes of hepatomegaly, splenomegaly, hepatosplenomegaly, lymphadenopathy, and massive hepatomegaly.

Causes of Hepatomegaly, Splenomegaly, Hepatosplenomegaly, Lymphadenopathy, and Massive Hepatomegaly

Causes of Hepatomegaly

Alcoholic and Toxic Liver Disease

• Alcoholic fatty liver disease presents with hepatomegaly, often asymptomatic, with leukocytosis and macrocytosis on blood tests 1
• Alcoholic hepatitis causes tender hepatomegaly with jaundice, fever, and AST/ALT ratio typically exceeding 2 1
• Drug-induced liver injury can cause hepatomegaly, though biliary obstruction and other alternative causes must be excluded 2

Acute Hepatic Injury

• Acute viral hepatitis (hepatitis A, B, C) causes hepatomegaly with moderate to marked aminotransferase elevation 1
• Ischemic liver injury (shock liver) from systemic hypoxia or hypotension leads to hepatomegaly and can progress to liver failure 1
• Acute hepatitis on CT demonstrates hepatomegaly in 52.9% of patients, along with periportal edema and gallbladder wall thickening 1

Chronic Liver Disease and Cirrhosis

• Alcoholic liver cirrhosis causes hepatomegaly early, though the liver may become atrophic in advanced stages, with spider angioma, gynecomastia, and portal hypertension complications 1
• Cirrhosis with portal hypertension from any etiology commonly causes hepatomegaly initially, though liver size may decrease as fibrosis progresses 3, 4
• Wilson disease can present with hepatomegaly and may show Kayser-Fleischer rings, neurological symptoms, or psychiatric manifestations 3, 5

Metabolic Storage Disorders

• Glycogen storage diseases frequently present with hepatomegaly, with fasting hypoglycemia as a key distinguishing feature 3, 5
• Lysosomal storage diseases commonly present with hepatomegaly, including Niemann-Pick disease, Gaucher disease, and lysosomal acid lipase deficiency 3, 6
• Acid sphingomyelinase deficiency (ASMD) presents with hepatomegaly and mixed dyslipidemia with decreased HDL 3, 4

Congestive and Vascular Causes

• Cardiac hepatopathy from right heart failure causes hepatomegaly with hepatic congestion visible on contrast-enhanced imaging 1, 2
• Hepatic vascular occlusion (hepatic arterial or portal venous) can cause hepatomegaly and may result in hepatic infarction 1

Infectious Causes

• Cytomegalovirus and Epstein-Barr virus infections can cause hepatomegaly with lymphocytic infiltration 2, 7
• Hepatitis B, C, and E are common infectious causes of hepatomegaly 2

Other Causes

• Cystic fibrosis hepatobiliary involvement presents with hepatomegaly, requiring annual screening 3
• Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis cause hepatomegaly 2

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Causes of Splenomegaly

Hepatic Diseases with Portal Hypertension

• Cirrhosis with portal hypertension is the most common hepatic cause of splenomegaly, often presenting with thrombocytopenia and hypersplenism 4, 5
• Non-cirrhotic portal hypertension (idiopathic non-cirrhotic portal hypertension/INCPH) causes significant splenomegaly more commonly than cirrhotic portal hypertension, with low liver stiffness (<12 kPa) on transient elastography 4, 5
• Wilson disease may present with isolated splenomegaly due to clinically inapparent cirrhosis with portal hypertension 3, 4
• Esophageal varices and ascites are commonly associated with splenomegaly from portal hypertension 4

Hematologic and Myeloproliferative Disorders

• Myeloproliferative disorders, particularly myelofibrosis, are associated with massive splenomegaly 3
• Polycythemia vera and essential thrombocythemia cause splenomegaly, with progression to post-PV or post-ET myelofibrosis defined by increasing splenomegaly ≥5 cm from left costal margin 4
• Hairy cell leukemia characteristically presents with splenomegaly, and resolution of palpable splenomegaly is required for complete remission 4
• Chronic myeloid leukemia (CML) presents with splenomegaly as a defining feature 4
• Chronic myelomonocytic leukemia (CMML) frequently presents with splenomegaly, though some patients develop massive splenomegaly 4

Lysosomal Storage Disorders

• Gaucher disease is the most common lysosomal storage disorder causing significant splenomegaly, affecting 90% of type 1 patients 4, 6
• Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) can present with massive splenomegaly (>10x normal size) 3, 4
• Niemann-Pick disease type C and lysosomal acid lipase deficiency (LALD) are associated with splenomegaly 4

Infectious Diseases

• Malaria and schistosomiasis are common causes of splenomegaly in tropical regions 4
• Visceral leishmaniasis (kala-azar) presents with chronic fever, weight loss, splenomegaly, pancytopenia, and hypoalbuminemia 4
• Cytomegalovirus infection can cause splenomegaly with chronic antigenic stimulation 7
• Endocarditis can lead to splenic abscess and splenomegaly 3

Autoimmune Disorders

• Rheumatoid arthritis with Felty syndrome causes splenomegaly 3, 4
• Systemic lupus erythematosus (SLE) may present with splenomegaly 4

Sickle Cell Disease

• Sickle cell disease can present with acute splenic sequestration characterized by sudden pallor and severe anemia, or chronic splenomegaly requiring splenectomy 4

Important Diagnostic Pitfall

• In idiopathic thrombocytopenic purpura (ITP), mild splenomegaly occurs in less than 3% of patients; moderate or massive splenomegaly essentially excludes ITP as a diagnosis 4, 5

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Causes of Hepatosplenomegaly

Metabolic Storage Disorders

• Lysosomal storage diseases commonly present with both hepatomegaly and splenomegaly, with Niemann-Pick disease showing significant hepatosplenomegaly, growth failure, hyperlipidemia, and characteristic storage cells 3, 6
• Acid sphingomyelinase deficiency (ASMD) presents with hepatosplenomegaly and can have massive splenomegaly (>10x normal size), often with a 4+ year diagnostic delay 3, 4
• Lysosomal acid lipase deficiency (LALD) presents with hepatosplenomegaly and dyslipidemia 3
• Gaucher disease causes hepatosplenomegaly in 90% of type 1 patients 4
• Glycogen storage diseases frequently present with hepatomegaly, with some types also causing splenomegaly 3, 4

Hepatic Diseases with Portal Hypertension

• Cirrhosis with portal hypertension from any cause commonly causes hepatosplenomegaly, with thrombocytopenia and other signs of hypersplenism 3, 5
• Wilson disease can present with hepatosplenomegaly due to clinically inapparent cirrhosis, particularly in young patients with Kayser-Fleischer rings or neurological symptoms 3, 5
• Non-cirrhotic portal hypertension causes significant hepatosplenomegaly more commonly than cirrhotic portal hypertension, with low liver stiffness (<12 kPa) on transient elastography 4, 5

Infectious Diseases

• HIV infection commonly presents with hepatosplenomegaly, with 16.66% showing hepatomegaly and 9.47% showing splenomegaly, often due to Mycobacterium tuberculosis infection 8
• Cytomegalovirus infection can cause hepatosplenomegaly with lymphocytic infiltration of hepatic sinusoids 7
• Visceral leishmaniasis presents with hepatosplenomegaly, chronic fever, weight loss, and pancytopenia 4
• Malaria and schistosomiasis in tropical regions cause hepatosplenomegaly 4

Hematologic Malignancies

• Hepatosplenic alpha/beta T-cell lymphoma can masquerade as cirrhosis with hepatosplenomegaly, diffuse lymphadenopathy, and diffuse infiltration of liver parenchyma 9
• Myeloproliferative disorders cause hepatosplenomegaly, particularly myelofibrosis 3
• Chronic myeloid leukemia presents with hepatosplenomegaly 4

Other Causes

• Cystic fibrosis hepatobiliary involvement presents with hepatosplenomegaly, requiring annual screening with labs and physical examination 3
• Autoimmune disorders including rheumatoid arthritis with Felty syndrome cause hepatosplenomegaly 3

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Causes of Lymphadenopathy

Infectious Causes

• HIV infection presents with lymphadenopathy in 49.18% of patients, with bilateral discrete cervical, axillary, and inguinal lymphadenopathy being the most common presentation 8
• Mycobacterium tuberculosis infection is the most common cause of lymphoreticular involvement in HIV patients, with all 29 cases of abdominal lymphadenopathy having AIDS 8
• Epstein-Barr virus infection causes lymphadenopathy and can be associated with hepatosplenic T-cell lymphoma 9
• Cytomegalovirus infection causes lymphadenopathy 2

Hematologic Malignancies

• Hepatosplenic alpha/beta T-cell lymphoma presents with diffuse lymphadenopathy (axillary, retroperitoneal, and inguinal) along with hepatosplenomegaly 9
• Hairy cell leukemia presents with lymphadenopathy and splenomegaly 4

Hepatic Diseases

• Acute hepatitis demonstrates perihepatic lymphadenopathy (>7 mm) in 98.8% of patients on contrast-enhanced CT, with small hepatoduodenal lymphadenopathy being common 1

HIV-Associated Patterns

• HIV cases with lymphadenopathy and hepatomegaly have a significantly higher chance of having AIDS (32.54% vs 23.97%), with CD4 counts significantly lower in those with lymphadenopathy and hepatosplenomegaly 8
• Abdominal lymphadenopathy in HIV patients is strongly associated with AIDS and opportunistic infections 8

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Causes of Massive Hepatomegaly

Metabolic Storage Disorders

• Glycogen storage diseases frequently present with massive hepatomegaly, with fasting hypoglycemia as a key distinguishing feature 3, 5
• Lysosomal storage diseases, particularly Niemann-Pick disease and Gaucher disease, can cause massive hepatomegaly 3, 6

Acute Hepatic Injury

• Severe alcoholic hepatitis causes marked hepatomegaly with tender liver edge, jaundice, and fever 1
• Acute viral hepatitis with fulminant presentation can cause massive hepatomegaly 1

Hematologic Malignancies

• Hepatosplenic alpha/beta T-cell lymphoma causes massive hepatomegaly with diffuse sinusoidal infiltration that can mimic cirrhosis 9

Congestive Causes

• Severe cardiac hepatopathy from acute right heart failure causes massive hepatomegaly with hepatic congestion 1

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Key Diagnostic Approach Principles

Initial Laboratory Evaluation

• Complete blood count to assess for cytopenias (particularly thrombocytopenia indicating portal hypertension or hematologic disorders), liver function tests, lipid profile, blood glucose, lactate, and uric acid levels should be obtained 3, 5
• AST/ALT ratio <1 early but often reverses to >1 in advanced cirrhosis 5
• Mixed dyslipidemia with decreased HDL is common in storage disorders 4, 5

Imaging Studies

• Abdominal ultrasound is the first-line imaging modality to confirm hepatosplenomegaly, measure organ size, and assess for portal hypertension signs 1, 4, 5
• Liver elastography (transient elastography or shear wave elastography) to assess liver stiffness, with low liver stiffness (<12 kPa) despite significant splenomegaly suggesting non-cirrhotic portal hypertension rather than cirrhosis 4, 5
• Doppler ultrasonography to assess portal blood flow velocity and detect portal hypertension 5

Specialized Testing

• Genetic testing (SMPD1 gene for ASMD, JAK2V617F/MPL/CALR for myeloproliferative neoplasms) and enzymatic analysis should be considered based on clinical suspicion 3, 4, 5
• Flow cytometry for lymphoproliferative disorders (CD19, CD20, CD11c, CD25, CD103, CD123, CD200 for hairy cell leukemia) 4
• Bone marrow examination in patients older than 60 years or those with systemic symptoms 4, 5

Referral Pathways

• Patients with hepatosplenomegaly should be initially referred to a hepatologist or gastroenterologist, as the liver is often the primary affected organ 3, 5
• In patients with known bleeding disorders who develop hepatosplenomegaly, joint evaluation by both hepatologist and hematologist is recommended 3

Critical Pitfalls to Avoid

• Do not assume cirrhosis without considering lysosomal storage diseases in young adults with hepatosplenomegaly and normal or near-normal liver function tests, as these conditions often have a 4+ year diagnostic delay 5
• Do not diagnose ITP if moderate or massive splenomegaly is present, as this essentially excludes the diagnosis 4, 5
• Do not miss biliary obstruction, cholangitis, or choledocholithiasis as alternative causes when evaluating suspected liver disease 2
• In HIV patients with lymphadenopathy and hepatomegaly, investigate aggressively for opportunistic infections, particularly tuberculosis 8