Clinical manifestations 1. Symptoms. Subclinical pre-stage of hepatocellular carcinoma means that from the beginning of the lesion to the diagnosis of subclinical hepatocellular carcinoma, patients do not have clinical symptoms and signs, which are difficult to be detected clinically, and it usually takes about 10 months. In the subclinical stage (early stage) of hepatocellular carcinoma, the tumor is about 3-5cm, most patients still have no typical symptoms, and the diagnosis is still difficult, and most of them are detected by serum AFP screening, which lasts about 8 months on average, during which a few patients can have the symptoms related to chronic underlying liver diseases, such as epigastric stuffiness, abdominal pain, fatigue and loss of appetite. Therefore, for those who have high risk factors and experience the above conditions, they should be alerted to the possibility of hepatocellular carcinoma. Once typical symptoms appear, liver cancer is often in middle or advanced stage, at this time, the disease develops rapidly, about 3-6 months in total, and its main manifestations are: (1) Pain in liver area. Right upper abdominal pain is the most common, which is an important symptom of the disease. It is often intermittent or persistent vague pain, dull pain or distension, and intensifies with the development of the disease. The site of pain is closely related to the site of the lesion, the lesion located in the right lobe of the liver is pain in the right quaternary rib area, while the pain located in the left lobe of the liver is pain in the subxiphoid region; if the tumor invades the diaphragm, the pain can be dispersed to the right shoulder or the right back; the tumor that grows to the right rear can cause pain in the right lumbar region. The cause of pain is mainly due to the tautness of hepatic envelope caused by tumor growth. Sudden severe abdominal pain and peritoneal irritation may be caused by peritoneal irritation due to rupture and hemorrhage of subperitoneal cancer nodules. (2) Loss of appetite. Symptoms such as fullness in the epigastrium after meals, dyspepsia, nausea, vomiting and diarrhea are easy to be neglected due to lack of specificity. (3) Loss of weight and fatigue. Generalized weakness, a few advanced patients may present malignant fluid condition. (4) Fever. It is common, mostly persistent low-grade fever, around 37.5-38℃, or irregular or intermittent, persistent or tachyphylactic high grade fever, similar to liver abscess, but there is no chills before the fever, and antibiotic treatment is ineffective. Fever is mostly cancerous fever, which is related to the absorption of tumor necrotic material; sometimes it can be caused by cholangitis due to the compression or invasion of bile ducts by the cancer, or due to the combination of other infections with low resistance. (5) Symptoms of extrahepatic metastases. For example, lung metastasis can cause cough and hemoptysis; pleural metastasis can cause chest pain and bloody pleural effusion; bone metastasis can cause bone pain or pathological fracture. (6) Jaundice, hemorrhagic tendency (gums, nosebleed and subcutaneous bruise, etc.), upper gastrointestinal bleeding, hepatic encephalopathy and liver and renal failure are often seen in patients with advanced stage. (7) Paraneoplastic syndrome, i.e. endocrine or metabolic disorders caused by metabolic abnormality of liver cancer tissues or various effects of cancer tissues on the body. Clinical manifestations are diverse and lack of specificity, common ones include spontaneous hypoglycemia, erythrocytosis; others include hyperlipidemia, hypercalcemia, precocious puberty, gonadotropin secretion syndrome, cutaneous porphyria, abnormal fibrinogenemia and paraneoplastic syndrome, etc., but they are relatively rare. Signs. In the early stage of hepatocellular carcinoma, most patients do not have obvious positive signs, and only a few patients can find mild hepatomegaly, jaundice and itchy skin on physical examination, which should be non-specific manifestations of underlying liver disease. In middle and advanced hepatocellular carcinoma, jaundice, hepatomegaly (hard texture, uneven surface, with or without nodules, vascular murmur) and peritoneal effusion are common. If there is a background of hepatitis or cirrhosis, liver palms, spider nevus, red nevus, varicose veins of the abdominal wall and enlarged spleen can be found. (1) Enlargement of liver: it is often progressive, with hard texture, uneven surface, nodules of different sizes or even huge lumps, clear margins, and tenderness and pressure of varying degrees. When the liver cancer protrudes to the right subcostal arch or subcordate, the corresponding part can be seen as localized fullness and elevation; if the cancer is located in the diaphragmatic surface of the liver, the diaphragm is mainly confined to elevation and the lower edge of the liver may not be enlarged; the cancerous nodules located on the surface of the liver close to the lower edge are the easiest to be touched. (2) Vascular murmur: due to the rich and tortuous blood vessels of liver cancer, the arteries become thin suddenly or the cancer mass compresses the hepatic artery and abdominal aorta, about half of the patients can hear windy vascular murmur in the corresponding parts; this sign has important diagnostic value, but it is not significant for early diagnosis. (3) Jaundice: yellowing of the skin and sclera, which often appears in the late stage, mostly due to the bile duct obstruction caused by the compression of bile ducts by cancerous tumor or enlarged lymph nodes, and also due to the damage of liver cells. (4) Signs of portal hypertension: patients with hepatocellular carcinoma often have cirrhosis background, so they often have portal hypertension and enlarged spleen. Abdominal fluid is the manifestation of late stage, usually leakage fluid, bloody fluid is mostly caused by the cancer breaking into the abdominal cavity, and can also be caused by peritoneal metastasis; cancer thrombus in portal vein and hepatic vein can accelerate the growth of abdominal fluid. Infiltration and metastasis. (1) Intrahepatic metastasis: Hepatocellular carcinoma initially tends to spread intrahepatic metastasis, which is easy to invade portal vein and its branches and form tumor embolus, and cause multiple metastatic foci in the liver after detachment. If the tumor thrombus of portal vein branches is obstructed, it will often cause or aggravate the existing portal hypertension. (2) Extra-hepatic metastasis: ① hematogenous metastasis, the most common is lung metastasis, and it can also be transferred to pleura, adrenal gland, kidney and bone and other parts. Lymphatic metastasis, the most common is hepatic portal lymph node metastasis, which can also be transferred to pancreas, spleen and para-aortic lymph nodes, and occasionally involves supraclavicular lymph nodes. ③ Plantation metastasis is rare, but occasionally it can be planted in the peritoneum, diaphragm and thoracic cavity, causing bloody abdominal and thoracic effusion; women can have ovarian metastasis, which can result in the formation of larger lumps. 4.Common complications. (1) Upper gastrointestinal bleeding: hepatocellular carcinoma often has hepatitis and cirrhosis background accompanied by portal hypertension, and portal vein and hepatic vein thrombus can further aggravate portal hypertension, so it often causes bleeding from varicose vein cracking in the middle and lower esophagus or gastric fundus. If the cancer cells invade the bile duct, it may cause biliary hemorrhage, vomiting blood and black stool. Some patients may have extensive bleeding due to erosion of gastrointestinal mucosa, ulcer and coagulation dysfunction, and hemorrhage may lead to shock and hepatic coma. (2) Hepatopathic nephropathy and hepatic encephalopathy (hepatic coma): In the advanced stage of hepatocellular carcinoma, especially diffuse hepatocellular carcinoma, hepatic insufficiency or even failure can occur, which can cause hepatorenal syndrome (HRS), i.e. functional acute renal failure (FARF), which is mainly manifested by Significant oliguria and decreased blood pressure with hyponatremia, hypokalemia and azotemia, often progressive. Hepatic encephalopathy (HE), i.e. hepatic coma, is often a manifestation of terminal stage of hepatocellular carcinoma, which is often induced by gastrointestinal bleeding, large amount of diuretics, electrolyte disorders and secondary infection. (3) Hepatocellular carcinoma nodal rupture and bleeding is the most urgent and serious complication of hepatocellular carcinoma. Necrosis and liquefaction of cancer foci in late stage may rupture spontaneously or due to external force, therefore, it is advisable to palpate gently during clinical physical examination and do not press with force. Rupture of cancer nodule may be confined to the subperitoneum of liver, causing acute pain, rapid enlargement of liver, and localization of soft mass; if rupture enters into the abdominal cavity, it may cause acute abdominal pain and peritoneal irritation sign. A small amount of bleeding can be manifested as bloody peritoneal fluid, while a large amount of bleeding can lead to shock or even rapid death. (4) Secondary infection: Due to long-term consumption and bed rest, liver cancer patients’ resistance is weakened, especially when the white blood cell decreases after chemotherapy or radiotherapy, it is easy to be complicated by many kinds of infections, such as pneumonia, intestinal infection, fungal infection and sepsis.