Liver Cancer - Symptoms, Causes, Types, Complications and Prevention

Cancer develops when normally functioning cells undergo mutation and multiply out of control, forming a tumour mass and it can happen in any tissue. When hepatic cells (liver cells) proliferate (increase rapidly in number or multiply) out of control, it is called liver cancer. 

Both benign (non-cancerous) and malignant (cancerous) forms of tumours exist. If left untreated, a malignant tumour may quickly develop and metastasize (spread) to other organs. When a tumour is considered benign, it might still grow but will not metastasize.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and accounts for about 80% of all cases of liver cancer whereas Intrahepatic cholangiocarcinoma (bile duct cancer), Angiosarcoma, Hemangiosarcoma, Hepatoblastoma, Biliary cystadenocarcinoma and Undifferentiated embryonal sarcoma of the liver (UESL) are much less common or rare kind of liver cancer.

What is Liver and its functions? 

The liver is one of the important and largest parts of the body. It located towards the upper right-hand portion of the abdominal cavity.

At any one time, nearly 1 pint of blood (13% of total volume) is stored in the liver at any time. There are many functions of liver are found, few of them include: 

• Bile production – necessary for food digestion, especially fats
• Red blood cells apoptosis – The controlled cell death of red blood cells occurs in liver from which bilirubin is emerged. It forms the major part of bile juice. 
• Metabolism – of various products such as food, medicines blood etc
• Production of plasma proteins in blood 
• Cholesterol production
• Glycogenesis (excess glucose into glycogen for storage) 
• Processing of hemoglobin for use of its iron content (the liver stores iron)
• Ornithine cycle (conversion of poisonous ammonia to urea)
• Regulation of blood clotting etc.

Types of Liver cancer

There are broadly two types of liver cancers - primary and secondary liver cancers. 

• Most of the primary liver cancers originate from epithelial tissue of the liver and rarely from the non-epithelial tissue of the liver. 
• The secondary cancers include various cancers which originated from other organs such as pancreas, colon, stomach, breast, or lung and metastasized (spread) to liver.

The subtypes of primary and secondary liver cancers include:

Primary liver cancers

Secondary liver cancers

Metastasized cancers from other organs, such as: 

• Pancreas
• Colon
• Stomach
• Breast
• Lung

Most people with liver cancer are asymptomatic (don't have any symptoms) in the initial stages of the development, but those who have had it for a while may start to notice them as a result of the liver illness it causes. Patients show early signs and symptoms, which could include:

• Unwanted weight loss
• Loss of appetite
• Upper abdominal pain
• Nausea and vomiting
• Fatigue and general weakness
• Hematemesis (blood vomiting)
• Hypoglycemia (low blood sugar levels)
• Ascites (pain and distention in the abdomen)
• Hypercalcemia (increased calcium levels in body)
• Erythrocytosis (high concentration of red blood cells)
• Yellow discoloration of skin and eyes (jaundice)
• Encephalopathy (impaired brain functions due to viral infection / toxins / conditions)
• Chalky or white stools
  

Before the development of liver cancer can be understood, the usual degeneration stages of liver must be understood. 

Stage 1: Liver Inflammation: Swollen or inflamed liver as a natural response to injury. Nevertheless, the liver is able to repair itself. 

Stage 2: Liver Fibrosis: Liver scarring due to untreated inflammation, disrupting its functions. Once hepatocytes (liver cells) are replaced by scar tissue, the liver can’t be able to repair itself. External supplantation / medicines are necessary. 

Stage 3: Cirrhosis: Severe, irreversible scarring of the liver which can take several years to decades. Liver cirrhotic people are also more susceptible to developing liver cancer.

Stage 4: Liver Failure: Cease of hepatic function. Liver can’t be repaired by itself or even with medicines. Liver transplant is the only option for recovery.

Although the risk factors have been clearly elucidated, there isn’t much luck about the causes of liver cancer, but the multifactorial pathways have been established. 

Liver cirrhosis can contribute to the progression of liver cancer. Liver cirrhosis is can be caused by various components such as: 

• Necrosis (hepatic cell death)
• Fibrosis (accumulation of proteins due to repetitive/long-lasting injury or inflammation)
• Ongoing regeneration (continuous regeneration of liver cells, even when unnecessary)
  

In some cases, especially in Hepatitis B patients, liver fibrosis can trigger superfluous regeneration in the liver which can incite the development of liver cancer, even without the development of cirrhosis. This is called non-cirrhotic pathway of liver cancer.

Although Hepatitis C causes liver cancer through the context of cirrhosis, Hepatitis B on the other hand, can incite cancer as the viral DNA is integrated into the host creating the HBV X protein, which promotes cell proliferation (eventually causing cancer). 

Liver Cancer Risk Factors

Similar to most of the other types of cancers, liver cancer also has avoidable and non-avoidable risk factors. The various types of liver cancer risk factors include: 

• Hepatitis B, C and D infection
• Cirrhosis
• Diabetes
• Nonalcoholic steatohepatitis (NASH)
• Drinking too much alcohol
• Consuming tobacco
• Aflatoxin B1
• Butter yellow
• Nitrosamines
• Haemochromatosis
• Wilson's disease
• α-1-antitrypsin deficiency
• Prolonged immunosuppressive therapy in renal transplant patients
• Clonorchiasis 
• Schistosomiasis

Viral hepatitis infections 

Hepatitis B virus (HBV): One of the most common chronic infections worldwide, with high mortality. The geographical incidence patterns of liver cancer mostly follow that of HBV. The highest rates of HBV are seen in sub-Saharan Africa and East Asia. Around 2% of the Middle Eastern and the Indian subcontinent are infected with HBV.

Through contact with blood or body fluids during sexual intercourse the viral spread is done which induces mutation in the hepatocytes of the host thus paving the path for liver cancer. 

Hepatitis C virus (HCV): With 14 crores of infections worldwide, around 3,50,000–5,00,000 patients die of HCV or HVC induced liver cancer. Transmission can be limited with improved hygiene standards as it spreads from parenteral routes, invasive sexual practices. It is rarely transmitted from mother to child. The mechanisms underlying HCV-associated carcinogenesis include: 

• increased hepatocyte proliferation and steatosis (fat accumulation in liver)
• virus-induced inflammation and oxidative stress inducing mutations 
• effects of virus-induced host immune responses.

Hepatitis Delta virus (HDV): A satellite virus which depends on HBV for generation and propagation. HDV demonstrated pronounced inflammation and severe liver disease than HBV, accelerating the prognosis of fibrosis and cirrhosis and finally to liver cancer. 

Chronic liver disease 

Cirrhosis: Although there are cirrhotic and non-cirrhotic pathways of liver cancer, cirrhosis; especially macronodular post-necrotic cirrhosis, is the most prevalent cause of the cancer. About 60% of cirrhotic patients develop liver cell dysplasia (precancerous stage) characterised by: 

• cellular expansion (increased cell number due to cell growth and cell division.)
• nuclear hyperchromatism (excess chromatin/nuclear material) 
• multinucleate cells (cells with many nuclei)

Nonalcoholic steatohepatitis (NASH): The liver scarring and eventual cancer that may result from NASH which is the most severe form of nonalcoholic fatty liver disease (excess fat build-up in the liver). An inflammatory response and damage to liver cells may result in certain persons.

Diabetes mellitus

People specially with type-2 diabetes are at greater risk of developing nonalcoholic fatty liver disease (NAFLD) and chronic liver disease (CLD) further that can lead to liver cancer.

Habits

Alcoholism: About four-fold increased risk of liver cancer could be seen with in alcoholics when compared with teetotallers. It could act as a co-carcinogen in patients suffering with HBV or HCV.

Tobacco use: A higher risk of liver cancer can be linked to cigarette smoking. The number of pack years is directly proportional to the risk. 

Mycotoxins 

Mycotoxins are naturally occurring poisons generated by a wide variety of moulds (fungi). Many foods, especially cereals, dried fruits, nuts, and spices, are susceptible for mycotoxins growth. Mycotoxins are chemically stable and may thus remain in foods even after preparation.

Aflatoxins: the most poisonous mycotoxins - produced by Aspergillus flavus and Aspergillus parasiticus. Apart from the milk of animals that are fed contaminated feed, aflatoxin can also be seen in:

• cereals (corn, sorghum, wheat and rice)
• oil seeds (soybean, peanut, sunflower and cotton seeds)
• spices (chili peppers, black pepper, coriander, turmeric and ginger) 
• tree nuts (pistachio, almond, walnut, coconut and Brazil nut)

Acute poisoning (aflatoxicosis) caused by high levels exposure to aflatoxins can cause liver. Its carcinogenic effect, can induce DNA damage inciting liver cancer.

Fumonisins: Produced by Fusarium fungus, fumonisins it can grow in oats and maize. Studies have linked fumonisins to oesophageal cancer and suspicions for liver cancer

Chemical carcinogens 

A number of chemical carcinogens can induce liver cancer in experimental animals. These include butter-yellow and nitrosamines used as common food additives

Butter yellow: Butter yellow is a food dye when used in long term causes bile duct dilatation and hyperplasia (increased cell number) in adjacent hepatocytes.

Nitrosamines: chemicals produced by the reaction of nitrites and secondary amines used as food preservatives can cause liver cancers among various others.

Arsenic: In few geographical places, drinking water can contain arsenic naturally. Arsenic is also a part of vinyl chloride, used for certain plastics that can increase risk for liver cancer.

Inherited liver diseases

Haemochromatosis: a hereditary disorder of iron salts being deposited in the tissues, leading to liver damage, diabetes mellitus, bronze discoloration of the skin and finally liver cancer.

Wilson's disease (hepatolenticular degeneration): a hereditary (ATP7B gene) disorder of copper being deposited in the tissues of liver, brain and other vital organs, leading to liver and organ damage finally liver cancer.

Various other medical conditions

α-1-antitrypsin deficiency: an inherited condition in which α-1-antitrypsin that protects the lungs produced by the liver is not produced. This leads to lung and liver cancer.

Clonorchiasis: infection with the liver fluke Clonorchis sinensis usually due to undercooked freshwater fish. 

Schistosomiasis (also called bilharzia): a disease caused by parasitic worms.

Prolonged immunosuppressive therapy in renal transplant patients: can also increase liver cancer risk.

Excessive intake of male hormones or anabolic steroids: These hormones, for building muscle, are a risk factor.

Complications of Liver cancer

Liver cancer results in several complications as liver is the source of metabolism, enzyme activation, the storage of minerals and glucose, etc. Any abnormality in the liver leads to altered functions. Liver cancer may be caused by tumour pressure on the bile duct or other organs, hormones released by cancer cells, and liver malfunction resulting in a build-up of toxins in the body. Common complications of liver cancer, include: ·   

• Anaemia (lack of healthy red blood cells)
• Obstruction of bile duct   
• Increase in portal blood pressure (portal hypertension)
• Hypercalcemia (high blood calcium)   
• Hepatorenal Syndrome (occurrence of kidney disease due to the presence of liver disease) 
• Hepatic Encephalopathy

Liver Cancer Prevention

There are few established steps to know about how to prevent liver cancer? Various variables contribute to the development of cancer. Despite the fact that there is currently no perfect and proven method of preventing liver cancer, various steps have been elucidated by the researchers which can reduce the chances of its development, these include:

• Viral hepatitis prevention and vaccination: liver cancer can be prevented if viral hepatitis C can be prevented. A vaccine can protect healthy people from contracting hepatitis B. Blood must be tested before transfusion to avoid any contamination. 
• Cirrhosis treatment: it can be avoided by prompt treatment of the liver injury.
• Avoiding alcohol and tobacco consumption: Even liver injury can be avoided by abstinence from alcoholism and tobacco. 
• Maintain a healthy weight: Obesity prevention could be an additional line of defense against liver cancer. Fatty liver disease and diabetes are both risk factors for liver cancer, and both are more common in obese people.
• Limit exposure to cancer-causing chemicals: Changing the way certain grains are stored in tropical and subtropical countries could reduce exposure to cancer-causing substances such as aflatoxins. Many developed countries already have regulations to prevent and monitor grain contamination.

Liver Cancer Diagnosis

Based on the symptoms, liver specialist doctor might suggest the series of blood test and imaging tests to identify the stage of liver cancer, that include:

• Physical examination 
• Blood tests
• Ultrasonography
• Computed tomography (CT or CAT) scan
• Magnetic resonance imaging (MRI)
• Angiogram
• Liver Biopsy
• Biomarker testing of the tumour (also called as tumour molecular testing)

Liver Cancer Treatment

The various liver cancer treatment options include according to stage: 

• Surgery
• Radiofrequency ablation (RFA)
• Percutaneous ethanol injection
• Radiation therapy
• Chemoembolization 
• Radioembolization 
• Targeted therapy
• Immunotherapy
• Palliative care

Treatment according to liver cancer stage 

Early liver cancer

• Surgical Resection (Partial Hepatectomy)
• Adjuvant Therapy after Surgical Resection
• Liver Transplantation
• Locoregional Therapy

Intermediate stage

• Transarterial embolization 
• Radioembolization

Advanced stage

• Systemic Therapy