Table 3.

Potential coexisting disorders that must be considered in the diagnostic work-up of immune-related adverse events in patients with hepatocellular carcinoma.

Organ	iRAE	Chronic liver disease	Cancer	Others
Skin	• Pruritus • Rash • Erythema multiforme, psoriasis, urticaria and rosacea. • Severe cutaneous adverse reactions, including Steven-Johnson Syndrome, toxic epidermal necrolysis, and DRESS	• Pruritus • HCV- and HBV-related skin disorders, including lichen planus, polyarteritis nodosa, cryoglobulinaemic vasculitis, and porphyria cutanea tarda.	• Biliary tract obstruction due to liver nodules or hilar lymphadenopathies.	• Cutaneous toxicity from other medications
GI tract	• Diarrhoea • Colitis	• Small intestine bacterial overgrowth • Chronic pancreatitis	• HCC-associated diarrhoea	• Clostridium difficile • Antibiotic-induced dysbacteriosis • Lactulose-induced diarrhoea
Liver	• Hepatitis • AST/ALT elevation	• Flares or viral infection	• Tumour progression in the liver.	• Hepatotoxicity from other medications • Benign biliary obstruction
Lung	• Pneumonitis	• Hepatopulmonary syndrome • Porto-pulmonary hypertension	• Tumour progression in the lung.	• Pneumonia
Thyroid	• Hypothyroidism • Hyperthyroidism • Graves’ disease	• Reduced peripheral conversion of T4 to T3. • Thyroid dysfunction.
Adrenal glands and hypophysis	• Adrenal insufficiency • Hypophysitis	• Hypogonadism • Hypothalamic-pituitary dysfunction • Relative adrenal insufficiency • Hypogonadism	• Bilateral adrenal metastasis.	• Hyponatremia induced by diuretics
Kidney	• Nephritis	• Hepatorenal syndrome • HCV-related glomerulonephritis (mixed cryoglobulinemia) • HBV-related nephropathy • IgA nephropathy		• Iodinated contrast agents • Renal dysfunction induced by diuretics
Nervous system	• Encephalitis • Aseptic meningitis • Peripheral neuropathy • Myasthenia gravis • Guillain-Barre syndrome • Autonomic neuropathy • Transverse myelitis	• Porto-systemic encephalopathy (typical and atypical) • Viral-related peripheral neuropathy • Wernicke’s encephalopathy • Autonomic neuropathy associated to HCV infection	• Tumour progression in the brain or bone (spine). • Carcinomatous meningitis • Paraneoplastic hypercalcemia.	• Opiates, psychotropic drugs
Blood and bone marrow	• Cytopenias • Haemolytic anaemia • Red cell aplasia • Bone marrow failure • Haemophilia A • Hemophagocytic lymphohistiocytosis • Macrophage activation syndrome	• Hypersplenism and bone marrow depression • Anaemia due to folate or iron deficiency • Haemolytic anaemia • Viral-related thrombotic thrombocytopenic purpura and aplastic anaemia. • Immune thrombocytopenia associated with HCV infection. • Lymphopenia related to HCC therapies such as internal or external radiation	• Tumour bleeding • Bone marrow involvement	• Heparin-induced thrombocytopenia

DRESS (drug rash with eosinophilia and systemic symptoms). ALT, alanine aminotransferase; AST, aspartate aminotransferase; GI, gastrointestinal; T3, triiodothyronine; T4, thyroxine.