Liver Cancer (Hepatocellular Carcinoma): Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide, with approximately 906,000 new cases and 830,000 deaths annually. Hepatocellular carcinoma (HCC) accounts for approximately 75-85% of primary liver cancers; intrahepatic cholangiocarcinoma (iCCA) accounts for most of the remainder. HCC arises almost exclusively in the setting of underlying chronic liver disease — cirrhosis is present in approximately 80-90% of HCC cases. The three major risk factors are chronic hepatitis B virus infection (dominant globally), chronic hepatitis C virus infection (dominant in Western countries and Japan), and non-alcoholic fatty liver disease/metabolic-associated steatotic liver disease (MASLD/MAFLD, rapidly increasing). Alcohol-related cirrhosis, aflatoxin B1 exposure (a mycotoxin in contaminated cereals in parts of Africa and Asia), and hereditary hemochromatosis are additional risk factors. HCC surveillance with ultrasound plus alpha-fetoprotein every 6 months in high-risk populations (cirrhosis, chronic HBV) enables early detection when curative treatment is feasible. The Barcelona Clinic Liver Cancer (BCLC) staging system integrates tumor characteristics, liver function (Child-Pugh score), and performance status to guide treatment allocation.

Chronic HBV infection causes HCC through direct oncogenic integration of HBV DNA into the hepatocyte genome (particularly disrupting TP53 and beta-catenin/CTNNB1) and through HBx protein-mediated promotion of cell proliferation and inhibition of apoptosis. HCC can develop in HBV-infected patients without cirrhosis, unlike HCV-associated HCC. Chronic HCV infection is predominantly an indirect carcinogen, causing HCC through the development of cirrhosis and associated chronic inflammation, oxidative stress, and aberrant hepatocyte regeneration. Direct-acting antiviral (DAA) therapy achieving sustained virological response in HCV reduces but does not eliminate HCC risk in patients who have already developed cirrhosis. Non-alcoholic steatohepatitis (NASH) cirrhosis is the fastest-growing HCC risk factor in Western countries, driven by the obesity and type 2 diabetes epidemic. Aflatoxin B1 (produced by Aspergillus species in improperly stored grains) causes specific TP53 R249S mutations and dramatically amplifies HBV-attributable HCC risk. Hereditary hemochromatosis, primary biliary cholangitis, autoimmune hepatitis, and alpha-1 antitrypsin deficiency leading to cirrhosis confer elevated HCC risk.

Early HCC detected through surveillance is typically asymptomatic. Symptomatic presentation reflects either the hepatic mass itself or decompensation of the underlying cirrhotic liver. Right upper quadrant (RUQ) pain or discomfort — dull or aching in character — from hepatic capsule stretching occurs as HCC enlarges. Unexplained weight loss, progressive fatigue, and anorexia are common systemic symptoms. Sudden onset of severe abdominal pain with hemodynamic instability may indicate spontaneous rupture of an HCC nodule into the peritoneum — a rare but life-threatening complication requiring emergency management. Jaundice, ascites, and encephalopathy reflect hepatic decompensation, either from progressive liver parenchyma destruction by HCC or from portal vein thrombosis (portal hypertension progression). Paraneoplastic syndromes are uncommon but include hypoglycemia (insulin-like growth factor production), hypercalcemia (PTHrP secretion), erythrocytosis (ectopic erythropoietin), and watery diarrhea. A palpable, hard liver edge or a hepatic friction rub may be detected on physical examination.

HCC diagnosis in cirrhotic patients is established non-invasively by characteristic imaging features without biopsy when a liver mass shows typical arterial enhancement followed by portal venous washout on CT or MRI using the LI-RADS (Liver Imaging Reporting and Data System) 5 (definitely HCC) designation. LI-RADS 4 (probably HCC) and LI-RADS 3 require additional imaging, biopsy, or follow-up. AFP is elevated (greater than 20 ng/mL) in approximately 60-70% of HCC cases; AFP greater than 400 ng/mL plus typical imaging is diagnostic per AASLD criteria. PIVKA-II (protein induced by vitamin K absence or antagonist II, also called des-gamma-carboxyprothrombin, DCP) has superior sensitivity to AFP for HCC, particularly for portal venous invasion and BCLC advanced-stage HCC. The BCLC staging system (BCLC 0/A: very early/early, single HCC less than 5 cm, Child-Pugh A-B, PS 0; BCLC B: intermediate, multifocal, no vascular invasion; BCLC C: advanced, portal vein invasion, extrahepatic spread; BCLC D: end-stage, Child-Pugh C, PS 3-4) guides treatment allocation. Liver function is assessed by Child-Pugh score (A/B/C) and MELD score. Percutaneous image-guided core needle biopsy is performed for atypical lesions in non-cirrhotic patients or when non-invasive criteria are not met.

BCLC 0/A (early, curative): Surgical resection — anatomic hepatectomy with adequate future liver remnant (FLR) — is preferred for non-cirrhotic HCC and selected cirrhotic patients with Child-Pugh A and portal pressure less than 10 mmHg. Five-year OS exceeds 70% for BCLC A-0. Liver transplantation within Milan criteria (single HCC up to 5 cm or up to 3 nodules up to 3 cm, no vascular invasion) achieves 5-year OS of approximately 70-75% and cures both HCC and the underlying liver disease simultaneously. Locoregional ablation — radiofrequency ablation (RFA) or microwave ablation (MWA) for HCC up to 3 cm — achieves complete tumor ablation comparable to resection for small tumors with PS 0-1. BCLC B (intermediate, multinodular, no vascular invasion): Trans-arterial chemoembolization (TACE) with doxorubicin-eluting beads or conventional TACE (cTACE) is the standard; selective internal radiation therapy (SIRT/Y-90 radioembolization) is used in selected cases. BCLC C (advanced, portal vein invasion, extrahepatic spread): Atezolizumab 1200 mg plus bevacizumab 15 mg/kg IV every 3 weeks is the preferred first-line systemic therapy (IMbrave150: OS 19.2 vs 13.4 months vs sorafenib). Sorafenib 400 mg twice daily (SHARP trial: median OS 10.7 vs 7.9 months) is alternative. Durvalumab plus tremelimumab (HIMALAYA trial), lenvatinib (REFLECT trial, non-inferior to sorafenib), and hepatic arterial infusion chemotherapy (HAIC) are alternatives.

Prognosis is determined by tumor burden, hepatic function reserve, and performance status. BCLC 0/A (very early/early): 5-year OS greater than 70% with surgical resection or ablation. Milan-criteria liver transplant: 5-year OS approximately 70-75%. BCLC B (intermediate): median OS approximately 20 months with TACE. BCLC C (advanced): historical median OS with sorafenib approximately 10-12 months; atezolizumab-bevacizumab improves median OS to approximately 19 months. BCLC D (end-stage, Child-Pugh C): median survival under 3 months; best supportive care is recommended. AFP greater than 200 ng/mL, microvascular invasion, satellite nodules, and portal vein tumor thrombus predict worse outcomes. The prognosis for Liver Cancer (Hepatocellular Carcinoma): Causes, Symptoms, Diagnosis and Treatment varies depending on severity at diagnosis, the patient's overall health, and how promptly treatment is initiated. With early diagnosis and appropriate management, many patients achieve good outcomes and maintain quality of life. Regular follow-up with healthcare providers is essential to monitor progress, adjust treatment as needed, and detect any complications early. Adherence to prescribed treatments and lifestyle modifications significantly improves long-term prognosis.

HBV vaccination is the most effective HCC prevention strategy globally: universal infant HBV vaccination (3-dose Engerix-B or Recombivax series) provides lifelong protection against HBV infection and dramatically reduces HCC incidence in vaccinated birth cohorts. HBV-infected patients with active viral replication (HBV DNA detectable) should receive antiviral therapy (entecavir 0.5 mg/day or tenofovir 300 mg/day) to suppress HBV DNA to undetectable levels, which reduces HCC incidence by approximately 50-70%. HCV eradication with direct-acting antiviral therapy (sofosbuvir-ledipasvir, sofosbuvir-velpatasvir, glecaprevir-pibrentasvir, 8-12 weeks oral therapy) achieves sustained virological response in greater than 95% of patients and reduces HCC risk, though does not eliminate it in cirrhotic patients. NASH prevention through lifestyle modification (weight loss, exercise, Mediterranean diet), and treatment of type 2 diabetes and dyslipidemia addresses the fastest-growing HCC risk population. Aflatoxin B1 exposure is minimized by proper grain storage and handling. HCC surveillance with liver ultrasound plus AFP every 6 months is recommended for all cirrhotic patients and HBV carriers over age 40.

All patients with known cirrhosis from any cause (hepatitis B, hepatitis C, alcohol, NASH, or other) should be enrolled in a 6-monthly HCC surveillance program with liver ultrasound and AFP with their hepatologist or gastroenterologist. Any new hepatic nodule detected on surveillance imaging — even if small — requires further characterization with contrast-enhanced CT or liver MRI within 1 month and should not be dismissed without formal radiological evaluation using LI-RADS criteria. Seek urgent evaluation for sudden severe right upper quadrant or epigastric pain, hypotension, or signs of acute blood loss in a patient with known liver disease or HCC, as these may indicate spontaneous HCC rupture requiring emergency intervention. Unexplained weight loss, progressive fatigue, jaundice, or rapid increase in abdominal girth (ascites) in a patient with chronic liver disease requires prompt hepatology evaluation for possible HCC or hepatic decompensation. Patients with chronic HBV or HCV who have not yet been evaluated by a hepatologist should seek referral to determine whether they have fibrosis or cirrhosis, and whether they require antiviral therapy to prevent HCC development.