Update to Risk Factors for Hepatocellular Carcinoma : 1 Update to Risk Factors for Hepatocellular Carcinoma Assoc Prof Biochemistry : 2 Assoc Prof Biochemistry Leader of HCC Res Team ,Biochem Dept , College of Pharmacy, Minia University, Egypt
(E-Mail : firstname.lastname@example.org) Dr Nabil Mohie Adel-Hamid Introduction : 3 Introduction HCC is the most common cancer
in many countries . Recently , HCC was noticed to be the 5th most common cancer in males , 8th common cancer in females and about 560,000 cases are discovered / year , more than 80% of them occur in the developing countries. Slide 4: 4 Having very poor prognosis , represents the 3rd leading cause of cancer death worldwide , more than one-half in China . Generally , HCC is more frequent in men and the incidence increases with age . Slide 5: 5 Like other cancers , it is a multi-step process , involving many genetic alterations , that eventually , leads to malignant transformation of the hepatocytes. Most of liver diseases including chronic hepatitis lead to cirrhosis. Within 15 – 40 years . Slide 6: 6 Mostly, HCC develops among 70-90 % of cirrhotic patients, while only 10 % of HCC patients have non-cirrhotic liver, nor inflammatory lesions.
In WHO mortality data base of early 1980s surveillances , the highest rates were found in Mexico and Chile, then , France, Italy, Portugal, Austria, Hungary and Romania . Slide 7: 7 Unfortunately, figures are rising in many European countries, including UK, Wales and Scotland , mostly due to increased consumption of alcohol . Alcoholic liver diseases and hepatitis C infection – being primary etiologies for liver cirrhosis - are major causes of the rising HCC mortality rates . Pathogenesis of Human HCC : 8 Pathogenesis of Human HCC Being implicated in more than 70% of HCC cases world wide , liver cirrhosis is the major risk factor for HCC development . Liver carcinogenesis may last for decades , through progressive accumulation of different genetic alterations eventually lead to malignant transformation . Slide 9: 9 Thus , chronic liver injury initiates increased liver cell turnover , triggering oxidative DNA damage and inflammatory events . This leads to formation of dysplastic and macroregenerative nodules which are considered to be neoplastic nodules . The underlying steps in human hepatocarcinogenesis : 10 The underlying steps in human hepatocarcinogenesis 1- Irregular expression of ß-catenin :
It is a nuclear protein, regulating cell cycle , resulting from ß-catenin gene mutations . As well as , Wnt signaling pathway alteration plays a role in more than 50% of HCCs. Slide 11: 11 Wnt (wingless integration genes) molecules are large family of cysteine-rich secreted glycoproteins that control development in organisms ranging from nematodes to mammals. Slide 12: 12 Interestingly , intranuclear ß-catenin accumulation complexes to some other proteins as Wnt ligands and Frizzled receptor leading to unrestricted cell cycling : Slide 13: 13 2- Up-regulation of many growth factors : 14 2- Up-regulation of many growth factors As insulin-like growth factor (IGF) , insulin receptor substrate 1 , hepatocyte growth factor (HGF) and transforming growth factor ß (TGF- ß) have been involved in the development of HCC . 3- Transformation from pre-neoplastic to HCC nodules: : 15 3- Transformation from pre-neoplastic to HCC nodules: It is always accompanied by neo-vascularization , HCC is a highly vascular tumor . Thus , over expression of the angiogenic factors ,vascular endothelial growth factor (VEGF) and angiopoietin-2 , is another pathway for HCC genesis . 4- Mutations in transcription factors controlling cell cycle: : 16 4- Mutations in transcription factors controlling cell cycle: it also participate in hepatocellular carcinogenesis . These factors , are phospho-retinoblastoma (pRb),P53 , transforming growth factor (TGF-ß) and ß- catenin . Mutations in these factors deprive the cell from controlling cycling , leading to crazy mitosis and cancer Risk factors for HCC and different pathways of pathogenesis .NASH=non-alcoholic steatohepatitis ,CH= chronic hepatitis. : 17 Risk factors for HCC and different pathways of pathogenesis .NASH=non-alcoholic steatohepatitis ,CH= chronic hepatitis. Risk factors for HCC : 18 Risk factors for HCC I- Hepatitis B virus (HBV)- infection :
This DNA virus is the most frequent etiology of liver cancer . There was a strong epidemiological evidence correlating HCC to HBV infection , shown by positive results in HCC patients for both HB surface antigen (HBs Ag) and HB core antibodies (HBc antibodies ) or both together . Slide 19: 19 Patients negative to hepatitis B serum markers , although showing symptoms of chronic hepatitis or cirrhosis , were proved to have active intrahepatic replicating virus. This was conventionally known as occult HBV infection . II- Hepatitis C virus (HCV) infection : 20 II- Hepatitis C virus (HCV) infection In developing countries, the major concern in HCC frequently belongs to HCV long lasting infection. Chronic HCV infection mostly leads to hepatic cirrhosis before developing HCC. Additionally, occult HCV was observed in patients with chronic un-explained hepatitis . Slide 21: 21 Thus, both occult HBV and HCV infections contribute more or less to HCC prevalence due to the massive biopsy technique which is always the sole diagnostic tool in occult uncertain infections. Slide 22: 22 Generally, the prevalence of HCV-infection is accepted to be a horrible morbidifying factor in hepatic carcinogenesis.
In developing countries, the mode of transmission of HCV is diverse. Slide 23: 23 Old habits of injection , shaving , circumcision , blood transfusion, labor and surgical viral transmission, frequently created many infected generations who still for many years carry the infection although the modes of transmission were greatly minimized by hygienic and cultural development. Slide 24: 24 However, these old-infected populations constitute classic candidates for long standing infection, cirrhosis and HCC. Hepatitis C virus is a member of the Flaviviridae family of enveloped , positive- stranded RNA viruses , genus Hepacivirus. It is a completely cytoplasmic- replicating virus , that induces oncogenic transformation . Slide 25: 25 Most evidences show that HCV has a direct pathway in promoting malignant hepatocyte transfor-mation . It is also now establi-shed that many viral proteins are implicated in malignant transf-ormation and HCC development. Of these proteins, core proteins, NS3, NS4, were shown to have transformation potential in tissue culture . Slide 26: 26 These viral proteins , in addition to the viral RNA , interact with many host- cell factors, although still regulate the viral life cycle . They modulate host- cell activities as cell signaling , transcription , transformation , apoptosis , membrane rearrangement , vesicular trafficking and protein translation . Slide 27: 27 This ultimately misleads the host transcription factors , disturbing cell mitosis and protein synthesis ,with a result of carcinogenesis .
On the other hand , HCV core has immunosuppressive activities through interaction with the complement receptor C1qR on the T cells leading to chronic infection . Slide 28: 28 III-The third cause is transfusion - transmitted virus (TTV):
It is found in patients with HCV- related liver disorders. These viral DNA traces were only discovered by fine in situ PCR in liver biopsies , which could be described to be neither HBV nor HCV material . IV- Diabetes Mellitus as a late initiator to HCC : : 29 IV- Diabetes Mellitus as a late initiator to HCC : Liver cirrhosis (a functional liver damage) is characterized by decrease in serum albumin level than 4 g \ dl and increased prothrombin time , is always higher in HCC patients with diabetes , than among those without history of diabetes . Slide 30: 30 Thus , there is a positive correlation between the history of diabetes mellitus and HCC which was not confounded by any other HCC risk factor. Slide 31: 31 A number of possible mechanisms explained this association . Most non-insulin dependent diabetics depicted hyper-insulinemia.
So, insulin or its precursors may interact with liver cells to stimulate mitogenesis or carcinogenesis . Slide 32: 32 Another possible pathway is that P53 mutation (apoptotic factor ) was noticed frequently in HCC patients with diabetes rather than non-diabetics , this could provide an evidence for a molecular mechanism interpreting this common association . V- Hereditary haemochromatosis : 33 V- Hereditary haemochromatosis It is an autosomal recessive condition characterized by excessive iron deposition in hepatocytes due to an increased intestinal absorption. Thus, liver disease is the commonest cause of death in patients with hereditary haemochromatosis . Slide 34: 34 Among hemochromatotic patients, 6% of men and 1.5% of women are at absolute risk of liver cancer .
Cross-sectional study showed that progression to HCC among haemochromatotic patients is mostly variable from population to another , depending mainly on exposure to environmental factors that synergize the current underlying gene mutation . VI- A special regional risk factor is Schistosomiasis among Nile basin population as Egyptians : : 35 VI- A special regional risk factor is Schistosomiasis among Nile basin population as Egyptians : Many cross-sectional studies on wide Egyptian sectors frequently correlated between HCV infection and intravenous treatment for schistosomiasis , a serious predisposing factor for hepatic fibrosis . Many HCC cases were diagnosed among long standing bilharziasis VII- Exposure to chemical carcinogens : 36 VII- Exposure to chemical carcinogens a- Exposure to exogenous chemicals :
Environmental pollutants as aflatoxin B , a product of mold commonly contaminates badly stored foods as well as insecticides were reported to be classical sources for hepatocarcinogenesis . Slide 37: 37 Another known chemical carcinogens with occult nature are chlorination byproducts in drinking water . Uncontrolled water chlorination converts many organic traces in water into dangerous intermediates as di-and tri- chloroacetic acids , which were experimentally known to induce HCC . Slide 38: 38 Additional rarely known chemical contaminant to drinking water, is an algal toxin , microcystin , which was found in pond-ditch waters , it induced primary liver cancer . However , many other chemical contaminants , solvents, food additives , drugs and hormones are thought to contribute to HCC. Slide 39: 39 b- Exposure to endogenous chemicals :
Recent studies strongly provided that bile acids may be pro-inflammatory and oncogenic agents. Thus , chronic exposure to bile acids plays an important role in inflammation and hepato- and cholangiocellular carcinogenesis . VIII- Alcoholism : 40 VIII- Alcoholism It is a very common source for steatohepatitis (fatty liver ), cirrhosis and eventually HCC .
In developed countries , it is the most common source for HCC, either directly after its oxidation into acetaldehyde (a genotoxic) or indirectly through developing cirrhosis .
Epidemiologically, there is a strong synergistic effect of alcohol on both viral infections with B or C in developing HCC . IX- Congenital disorders : 41 IX- Congenital disorders Alpha-1-antitrypsin deficiency(an acute-phase protein produced by liver cells) and tyrosinemia may be complicated by the development of HCC . Dietary or pharmacological management of hereditary tyrosinemia may offer a strategy for prevention of HCC in these cases . Slide 42: 42 Hereditary deficiency of this protein is mostly due to liver production of abnormal protein that can not be released into the plasma. Accumulation of the protein in hepatocytes can lead to liver damage . This can trigger hepatitis in neonates , end-stage liver disease , cirrhosis and HCC in adults . Slide 43: 43 Slide 44: 44 Morphology of Liver with Cancer : 45 Morphology of Liver with Cancer Post-Cancer Symptoms : 46 Post-Cancer Symptoms Slide 47: 47 Thank You