Liver Cancer (Hepatocellular Carcinoma): Causes

Pathogenesis (development of disease)

Heptocellular carcinoma (HCC; hepatocellular carcinoma) develops – usually at the base of liver cirrhosis – from degenerated hepatocytes (liver cells) or their precursors. Liver cirrhosis is mainly caused by hepatitis B or C infection. However, chronic alcohol abuse (alcohol abuse) or fatty liver (steatosis hepatis) can also be precursors for this disease.In hepatocellular carcinoma, different types of growth are distinguished: diffuse infiltrative (diffuse distribution of the tumor throughout the liver), multifocal (tumor spread over several tumor nests), and unifocal (single tumor).

Etiology (causes)

Biographic causes

  • Genetic burden – genetic defects (rare).
    • Genetic diseases
      • Alpha-1-antitrypsin deficiency (AATD; α1-antitrypsin deficiency; synonyms: Laurell-Eriksson syndrome, protease inhibitor deficiency, AAT deficiency) – relatively common genetic disorder with autosomal recessive inheritance in which too little alpha-1-antitrypsin is produced because of a polymorphism (occurrence of multiple gene variants). A deficiency of protease inhibitors is manifested by a lack of inhibition of elastase, which causes the elastin of the pulmonary alveoli to degrade. As a result, chronic obstructive bronchitis with emphysema (COPD, progressive airway obstruction that is not fully reversible) occurs. In the liver, the lack of protease inhibitors leads to chronic hepatitis (liver inflammation) with transition to liver cirrhosis (non-reversible damage to the liver with pronounced remodeling of the liver tissue). The prevalence (disease frequency) of homozygous alpha-1 antitrypsin deficiency is estimated at 0.01-0.02 percent in the European population.
      • Citrullinemia – autosomal recessive inherited metabolic disease of the so-called urea cycle, which serves the synthesis of urea; defect of the enzyme arginine succinate synthetase in the urea cycle.
      • Glycogen storage diseases – group of diseases with both autosomal dominant and autosomal recessive inheritance in which glycogen stored in body tissues cannot be degraded or converted to glucose, or can only be degraded incompletely.
      • Hemochromatosis (iron storage disease) – genetic disease with autosomal recessive inheritance with increased deposition of iron as a result of increased iron concentration in the blood with tissue damage.
      • Hereditary tyrosinemia – congenital, autosomal recessive inherited defect in tyrosine metabolism, which massively damages the liver, kidneys and peripheral nervous system.
      • Wilson’s disease (copper storage disease) – autosomal recessive inherited disease in which copper metabolism in the liver is disturbed by one or more gene mutations.
      • Porphyria cutanea tarda (PCT) – congenital (autosomal-dominant inheritance) or acquired metabolic disorder (enzymopathy); associated with liver and skin changes.
  • Socioeconomic factors – low socioeconomic status.

Behavioral causes

  • Nutrition
    • Too little fish consumption; inverse correlation between fish consumption and risk of disease.
    • Diets high in nitrates and nitrites, such as cured or smoked foods:Nitrate is a potentially toxic compound: Nitrate is reduced to nitrite in the body by bacteria (saliva/stomach). Nitrite is a reactive oxidant that reacts preferentially with the blood pigment hemoglobin, converting it to methemoglobin. Furthermore, nitrites (also contained in cured sausage and meat products and ripened cheese) form nitrosamines with secondary amines (contained in meat and sausage products, cheese and fish), which have genotoxic and mutagenic effects. They promote, among other things, the development of liver cancer (hepatocellular carcinoma).The daily intake of nitrate is usually about 70% from the consumption of vegetables (lamb’s lettuce and lettuce, green, white and Chinese cabbage, kohlrabi, spinach, radishes, radishes, beet), 20% from drinking water (nitrogen fertilizer) and 10% from meat and meat products and fish.
    • Consumption of food contaminated with aflatoxin.
  • Consumption of stimulants
    • Alcohol – (woman: > 40 g/day; man: > 60 g/day) (7.3-fold).
    • Tobacco (smoking) (1.4-fold)
    • Combined soft drinks, ie, containing sugar and sweeteners, >6 glasses per week; was positively correlated with risk for HCC
  • Taking anabolic steroids
  • Overweight (BMI ≥ 25; obesity) (+ 80%); increase + 24%; metabolic disorders (2.8-fold).

Disease-related causes

  • Adeno-associated virus 2 – possibly triggering a variant of hepatocellular carcinoma that occurs without prior cirrhosis.
  • Chronic alcohol dependence
  • Chronic hepatitis B or C (60-fold) – liver inflammation caused by the hepatitis B or C virus.
  • Diabetes mellitus; metabolic disorders (2.8-fold).
  • Liver cirrhosis (liver shrinkage) of any genesis [80-90% of cases!]
  • Metabolic syndrome – clinical name for the symptom combination obesity (overweight), hypertension (high blood pressure), elevated fasting glucose (fasting blood sugar) and fasting insulin serum levels (insulin resistance) and dyslipidemia (elevated VLDL triglycerides, lowered HDL cholesterol). Furthermore, a coagulation disorder (increased tendency to clotting), with an increased risk of thromboembolism is also often detectable
  • Non-alcoholic steatosis hepatis (NASH; non-alcoholic fatty liver; fatty liver)Note: Liver cancer now arises less and less frequently from hepatitis B or C, but more often from NASH.
  • Primary biliary cholangitis (PBC, synonyms: non-purulent destructive cholangitis; formerly primary biliary cirrhosis) – relatively rare autoimmune disease of the liver (affects women in about 90% of cases); begins primarily biliary, i.e., at the intra- and extrahepatic (“inside and outside the liver”) bile ducts, which are destroyed by inflammation (= chronic non-purulent destructive cholangitis). In the longer course, the inflammation spreads to the entire liver tissue and eventually leads to scarring and even cirrhosis; detection of antimitochondrial antibodies (AMA); PBC is frequently associated with autoimmune diseases (autoimmune thyroiditis, polymyositis, systemic lupus erythematosus (SLE), progressive systemic sclerosis, rheumatoid arthritis); Associated with ulcerative colitis (inflammatory bowel disease) in 80% of cases; long-term risk of cholangiocellular carcinoma (bile duct carcinoma, bile duct cancer) is 7-15%; increased up to 31-fold for hepatobiliary carcinoma.

Medications

  • Aristolochic acids, a group of structure-like aromatic nitro compounds from Aristolochia species (natural plant constituent in many plants of the genus Aristolochia (“pipe flowers”), this genus includes about 400-500 species); may be present in Chinese medicinal herbs; may be a common cause of hepatocellular carcinoma in Taiwan and other East Asian countries.

Environmental pollution – intoxications (poisonings).

  • Ingestion of nitrosamines
  • Aflatoxin B (mold product) as well as other mycotoxins – toxic substances formed by fungi.
  • X-ray contrast agent Thoratrast – is no longer used today.
  • Carcinogens such as: Arsenic (latency period 15-20 years); Chromium (VI) compounds.

Note: Fibrolamellar carcinoma cannot be attributed to the above causes.