WEBVTT 1 00:00:00.390 --> 00:00:01.650 Hi, y'all. 2 00:00:01.650 --> 00:00:03.900 In this lecture, we'll be discussing the epidemiology 3 00:00:03.900 --> 00:00:05.580 of liver cancer. 4 00:00:05.580 --> 00:00:07.860 Our goals for this module are to review anatomy 5 00:00:07.860 --> 00:00:10.290 and function of the liver, to describe the global burden 6 00:00:10.290 --> 00:00:14.730 of liver cancer and to define hepatocellular carcinoma 7 00:00:14.730 --> 00:00:17.670 or HCC and its major risk factors. 8 00:00:17.670 --> 00:00:20.520 We'll also look at epidemiologic patterns 9 00:00:20.520 --> 00:00:23.940 of HCC and studies of HCC risk, 10 00:00:23.940 --> 00:00:27.150 as well as looking at primary prevention of HCC. 11 00:00:27.150 --> 00:00:29.940 We'll also look at the other major form 12 00:00:29.940 --> 00:00:32.320 of liver cancer, cholangiocarcinoma 13 00:00:33.360 --> 00:00:35.880 and we'll describe its risk factors. 14 00:00:35.880 --> 00:00:39.210 So to begin with, looking at the anatomy of the liver, 15 00:00:39.210 --> 00:00:40.290 we see that the liver receives 16 00:00:40.290 --> 00:00:41.790 a dual blood supply consisting 17 00:00:41.790 --> 00:00:43.170 of the hepatic portal vein 18 00:00:43.170 --> 00:00:44.763 and the hepatic arteries. 19 00:00:45.690 --> 00:00:47.520 Supplying approximately 75% 20 00:00:47.520 --> 00:00:49.170 of the liver's blood supply, 21 00:00:49.170 --> 00:00:51.750 the hepatic portal vein carries venous blood drain 22 00:00:51.750 --> 00:00:53.970 from the spleen, gastrointestinal tract 23 00:00:53.970 --> 00:00:55.620 and its associated organs. 24 00:00:55.620 --> 00:00:57.240 The hepatic arteries supply the remainder 25 00:00:57.240 --> 00:01:00.213 of the blood flow, approximately 25%, to the liver. 26 00:01:02.400 --> 00:01:04.830 We see that there's two separate 27 00:01:04.830 --> 00:01:07.560 and distinctly different forms of primary liver cancer. 28 00:01:07.560 --> 00:01:09.660 The first is called hepatocellular carcinoma 29 00:01:09.660 --> 00:01:12.878 and then it arises from the cells of the liver, per se, 30 00:01:12.878 --> 00:01:15.150 which we call hepatocytes. 31 00:01:15.150 --> 00:01:18.420 There's also cholangiocarcinoma or biliary cancer, 32 00:01:18.420 --> 00:01:20.040 which arises from the epithelial lining 33 00:01:20.040 --> 00:01:23.550 of the gallbladder or of the biliary ducts. 34 00:01:23.550 --> 00:01:25.560 Hepatocellular carcinoma is much more common 35 00:01:25.560 --> 00:01:26.940 than biliary cancer, accounting 36 00:01:26.940 --> 00:01:30.900 for approximately 93% of all primary liver cancers 37 00:01:30.900 --> 00:01:34.263 and each type has its own set of epidemiologic parameters. 38 00:01:35.130 --> 00:01:38.040 When we look at the incidence of hepatocellular carcinoma, 39 00:01:38.040 --> 00:01:40.890 we see it's the fifth most common malignancy in the world 40 00:01:42.000 --> 00:01:45.420 and the third most common cause of death due to cancer. 41 00:01:45.420 --> 00:01:47.520 Liver cancer has an extremely poor prognosis 42 00:01:47.520 --> 00:01:48.570 and nearly as many people die 43 00:01:48.570 --> 00:01:50.670 from the disease as are diagnosed 44 00:01:50.670 --> 00:01:53.970 and most hepatocellular carcinomas are non-resectable 45 00:01:53.970 --> 00:01:55.050 at the time of diagnosis 46 00:01:55.050 --> 00:01:58.590 and the disease is usually fatal within three to six months. 47 00:01:58.590 --> 00:02:00.570 Rates are highest in sub-Saharan Africa, 48 00:02:00.570 --> 00:02:03.720 your Eastern and southeastern Asia, and Melanesia, 49 00:02:03.720 --> 00:02:07.080 which is the South Pacific Islands north of Australia. 50 00:02:07.080 --> 00:02:09.750 Approximately 84% of new cases occur 51 00:02:09.750 --> 00:02:11.670 in low and middle income countries 52 00:02:11.670 --> 00:02:13.890 in areas where oncogenic liver viruses, 53 00:02:13.890 --> 00:02:18.180 like hepatitis B virus and hepatitis C virus are endemic. 54 00:02:18.180 --> 00:02:21.690 More than half of new cases are diagnosed in China. 55 00:02:21.690 --> 00:02:24.117 Chronic exposure to aflatoxins from multigrains 56 00:02:24.117 --> 00:02:26.880 and chronic alcohol abuse are also independent risk factors 57 00:02:26.880 --> 00:02:28.230 that can synergistically interact 58 00:02:28.230 --> 00:02:30.300 with oncogenic hepatitis viruses 59 00:02:30.300 --> 00:02:31.833 to markedly heighten the risk. 60 00:02:33.524 --> 00:02:35.220 Hepatocellular carcinoma shows 61 00:02:35.220 --> 00:02:37.110 two main epidemiologic patterns, 62 00:02:37.110 --> 00:02:39.330 the predominant one being in China, 63 00:02:39.330 --> 00:02:42.870 sub-Saharan Africa, Southeast Asia, and the Amazon Basin. 64 00:02:42.870 --> 00:02:45.120 In these regions, liver viruses are endemic 65 00:02:45.120 --> 00:02:46.800 and the initial infection usually occurs 66 00:02:46.800 --> 00:02:48.780 during the perinatal period. 67 00:02:48.780 --> 00:02:50.490 In the populations of these regions, 68 00:02:50.490 --> 00:02:53.070 hepatocellular carcinomas are diagnosed early in life, 69 00:02:53.070 --> 00:02:54.480 sometimes during adolescence 70 00:02:54.480 --> 00:02:57.840 and their peak incidence occurs before the age of 50. 71 00:02:57.840 --> 00:02:58.980 A less common pattern 72 00:02:58.980 --> 00:03:00.870 of late onset is evident in North America 73 00:03:00.870 --> 00:03:02.130 and Western Europe. 74 00:03:02.130 --> 00:03:03.720 In the populations of these regions, 75 00:03:03.720 --> 00:03:06.840 the onset of hepatocellular carcinoma occurs late in life, 76 00:03:06.840 --> 00:03:09.120 usually after the age of 60. 77 00:03:09.120 --> 00:03:10.950 This pattern is primarily a consequence 78 00:03:10.950 --> 00:03:12.570 of sustained damage to liver cells 79 00:03:12.570 --> 00:03:15.993 from chronic alcohol abuse or late onset viral hepatitis. 80 00:03:16.920 --> 00:03:18.480 In the US, liver cancer accounts 81 00:03:18.480 --> 00:03:21.780 for less than 1% of all primary cancers, and it's associated 82 00:03:21.780 --> 00:03:24.030 with chronic infectious and inflammatory processes 83 00:03:24.030 --> 00:03:25.110 in the liver. 84 00:03:25.110 --> 00:03:26.070 There's a peak incidence 85 00:03:26.070 --> 00:03:29.853 at 60 to 65 years when it's 60 per 100,000 people. 86 00:03:31.230 --> 00:03:34.367 Looking at the 2020 statistics in the US, 87 00:03:34.367 --> 00:03:39.150 the incidence rate was 9.5 per 100,000 people 88 00:03:39.150 --> 00:03:42.750 and the rate in men was 14.1 per 100,000 people. 89 00:03:42.750 --> 00:03:44.520 In women, there's an instance 90 00:03:44.520 --> 00:03:47.463 of 5.2 cases per 100,000 people. 91 00:03:48.630 --> 00:03:50.640 In regards to mortality, 92 00:03:50.640 --> 00:03:54.810 there's an overall mortality rate of 8.7 per 100,000 people 93 00:03:54.810 --> 00:03:59.163 with a rate of 12.9 in men and 4.8 per 100,000 in women. 94 00:04:00.420 --> 00:04:01.650 When we look at the pathogenesis 95 00:04:01.650 --> 00:04:03.060 of hepatocellular carcinoma, 96 00:04:03.060 --> 00:04:08.060 we see that there's a couple different mechanisms at play. 97 00:04:08.850 --> 00:04:10.800 So hepatocellular carcinoma is initiated 98 00:04:10.800 --> 00:04:12.840 and promoted by sustained recursive damage 99 00:04:12.840 --> 00:04:16.050 to hepatocytes due to infection by oncogenic liver viruses, 100 00:04:16.050 --> 00:04:19.110 chronic exposure to alpha toxins, chronic alcohol abuse 101 00:04:19.110 --> 00:04:21.390 or a combination of these factors. 102 00:04:21.390 --> 00:04:23.370 Cellular mechanisms involved 103 00:04:23.370 --> 00:04:26.498 in the pathogenesis include early fatty change, 104 00:04:26.498 --> 00:04:29.340 chronic inflammation and cell necrosis, 105 00:04:29.340 --> 00:04:31.620 wound healing and regeneration of hepatocytes 106 00:04:31.620 --> 00:04:33.420 and late stage fibrosis leading 107 00:04:33.420 --> 00:04:36.093 to the eventual formation of fibrotic nodules. 108 00:04:36.990 --> 00:04:41.040 This is also referred to as cirrhosis of the liver. 109 00:04:41.040 --> 00:04:42.360 So as I just mentioned, 110 00:04:42.360 --> 00:04:45.300 some risk factors include alcohol use, cirrhosis, 111 00:04:45.300 --> 00:04:47.730 viral hepatitis caused by hepatitis B 112 00:04:47.730 --> 00:04:51.270 and hepatitis C viruses, aflatoxin B1, 113 00:04:51.270 --> 00:04:54.450 and then there's also some infectious etiology 114 00:04:54.450 --> 00:04:57.030 by liver flukes. 115 00:04:57.030 --> 00:04:59.010 Also, environmental causes, 116 00:04:59.010 --> 00:05:02.730 exposure to polycyclic aromatic hydrocarbons and metastasis. 117 00:05:02.730 --> 00:05:07.730 That is the metastasizing of cancer 118 00:05:07.740 --> 00:05:10.563 from a distant site in the body to the liver. 119 00:05:11.580 --> 00:05:13.800 So first, to turn to liver viruses. 120 00:05:13.800 --> 00:05:16.200 We see that in high-risk areas where hepatitis B virus 121 00:05:16.200 --> 00:05:19.260 and hepatitis C virus are endemic, 10 to 20% 122 00:05:19.260 --> 00:05:23.970 of young individuals become chronic carriers of HPV or HCV. 123 00:05:23.970 --> 00:05:26.370 Among those who suffer from chronic viral hepatitis, 124 00:05:26.370 --> 00:05:30.240 the annual incidence rates per 100,000 range from 400 to 800 125 00:05:30.240 --> 00:05:34.110 for men and 120 to 180 for women. 126 00:05:34.110 --> 00:05:35.340 Among such individuals, 127 00:05:35.340 --> 00:05:37.920 the cumulative risk at developing hepatocellular carcinoma 128 00:05:37.920 --> 00:05:42.920 by age 65 years is nearly 35% in men and 10% in women. 129 00:05:43.410 --> 00:05:47.190 Hepatitis A, B and C all cause inflammation, necrosis 130 00:05:47.190 --> 00:05:49.410 and cirrhosis of the liver. 131 00:05:49.410 --> 00:05:50.430 Their signs and symptoms 132 00:05:50.430 --> 00:05:53.853 are abdominal pain, jaundice, SCTs, and relapsing fever. 133 00:05:54.750 --> 00:05:56.850 Risk factors for these viruses 134 00:05:56.850 --> 00:05:59.410 are exposure to contaminated blood, 135 00:05:59.410 --> 00:06:02.070 maternal fetal placental transmission 136 00:06:02.070 --> 00:06:05.883 and sexually transmitted causation. 137 00:06:07.170 --> 00:06:10.620 The diagnosis of these viruses is by antibodies, 138 00:06:10.620 --> 00:06:15.510 increased liver enzymes, jaundice, SCTs, or imaging studies 139 00:06:15.510 --> 00:06:18.810 and the treatment is diet, alcohol abstinence, palliation 140 00:06:18.810 --> 00:06:20.760 and liver transplant. 141 00:06:20.760 --> 00:06:23.370 So the relative risk of developing liver cancer is increased 142 00:06:23.370 --> 00:06:25.950 by more than 20 fold for those chronically infected 143 00:06:25.950 --> 00:06:28.200 with either HPV or HCV compared 144 00:06:28.200 --> 00:06:31.170 to non-infected individuals and more than a hundredfold 145 00:06:31.170 --> 00:06:33.840 for those infected by both viruses. 146 00:06:33.840 --> 00:06:35.640 Approximately 50 to 55% 147 00:06:35.640 --> 00:06:38.460 of hepatocellular carcinomas are caused by HPV 148 00:06:38.460 --> 00:06:41.610 and 20 to 25% by HCV. 149 00:06:41.610 --> 00:06:44.400 Since HPV causes far more infections than HCV, 150 00:06:44.400 --> 00:06:47.250 particularly in younger generations, 151 00:06:47.250 --> 00:06:49.710 the global pattern of chronic HPV infections 152 00:06:49.710 --> 00:06:52.713 roughly simulates the global distribution of liver cancer. 153 00:06:54.090 --> 00:06:59.090 So to turn to discuss hep B virus a little bit more. 154 00:06:59.280 --> 00:07:00.540 We see it's a virus. 155 00:07:00.540 --> 00:07:03.090 It affects humans and chimpanzees, 156 00:07:03.090 --> 00:07:05.940 and there is an effective vaccine available. 157 00:07:05.940 --> 00:07:09.690 There's also blood-to-blood transmission of the virus 158 00:07:09.690 --> 00:07:12.270 and as we've discussed, it causes liver inflammation, 159 00:07:12.270 --> 00:07:15.093 liver cirrhosis, and hepatocellular carcinoma. 160 00:07:15.960 --> 00:07:17.250 I would encourage you all to look 161 00:07:17.250 --> 00:07:19.500 at the slide notes for more information 162 00:07:19.500 --> 00:07:23.253 about the history and biology of hep B virus. 163 00:07:24.780 --> 00:07:29.220 We also see that there are differing rates 164 00:07:29.220 --> 00:07:31.260 of hep B virus in different countries, 165 00:07:31.260 --> 00:07:35.490 largely due to preventive factors uptake 166 00:07:35.490 --> 00:07:39.960 of hep B vaccines probably being the primary determinant 167 00:07:39.960 --> 00:07:42.003 of rates of transmission. 168 00:07:43.980 --> 00:07:45.180 So as I just mentioned, 169 00:07:45.180 --> 00:07:47.970 there's several methods of primary prevention. 170 00:07:47.970 --> 00:07:52.970 The key method really being the hepatitis B virus vaccine. 171 00:07:53.880 --> 00:07:55.350 So there's widespread immunization 172 00:07:55.350 --> 00:07:58.053 against HPV in children globally, 173 00:07:58.950 --> 00:08:03.950 and this widespread immunization led to a 49% decrease 174 00:08:05.820 --> 00:08:08.580 in hepatocellular carcinoma in birth cohorts in Taiwan 175 00:08:08.580 --> 00:08:12.270 and a 42% decrease in hepatocellular carcinoma 176 00:08:12.270 --> 00:08:14.460 in birth cohorts in Korea. 177 00:08:14.460 --> 00:08:16.140 These vaccines target the viral envelope 178 00:08:16.140 --> 00:08:19.050 and provide long-term immunity against HPV infection, 179 00:08:19.050 --> 00:08:21.603 as well as protection against liver carcinogenesis. 180 00:08:24.480 --> 00:08:27.915 Turning to hepatitis C virus, we see that there's 150 181 00:08:27.915 --> 00:08:30.450 to 200 million people worldwide infected. 182 00:08:30.450 --> 00:08:32.880 It also infects humans in chimpanzees, however, 183 00:08:32.880 --> 00:08:34.533 no vaccine is available. 184 00:08:35.940 --> 00:08:40.640 We see that one key prevention technique 185 00:08:42.780 --> 00:08:43.770 that has limited the spread 186 00:08:43.770 --> 00:08:46.080 of hepatitis C virus has been the screening 187 00:08:46.080 --> 00:08:50.460 of donor blood because hepatitis infection 188 00:08:50.460 --> 00:08:54.363 from blood transfusion used to be more common. 189 00:08:55.920 --> 00:08:58.590 We also see the seroprevalence of HCV. 190 00:08:58.590 --> 00:09:00.570 That is the number of individuals infected 191 00:09:00.570 --> 00:09:02.310 with hepatitis C virus is highest 192 00:09:02.310 --> 00:09:06.213 in certain countries of Africa, Asia, and South America. 193 00:09:07.200 --> 00:09:08.970 It's also interesting 194 00:09:08.970 --> 00:09:12.810 that Egypt has the highest seroprevalence, 20%, 195 00:09:12.810 --> 00:09:14.940 which may have resulted from accidental transmission 196 00:09:14.940 --> 00:09:16.740 in a now discontinued mass campaign 197 00:09:16.740 --> 00:09:20.910 of paternal treatment of schistosomiasis. 198 00:09:20.910 --> 00:09:25.910 Schistosomiasis is a key neglected tropical disease caused 199 00:09:27.060 --> 00:09:29.385 by schistosomes, a kind of parasite 200 00:09:29.385 --> 00:09:32.760 that completes its lifecycle in reverse snails. 201 00:09:32.760 --> 00:09:36.300 So in many areas of Egypt where communities live close 202 00:09:36.300 --> 00:09:39.600 to the Nile and swim or bathe in the Nile, 203 00:09:39.600 --> 00:09:43.440 it's common to see schistosomiasis infection. 204 00:09:43.440 --> 00:09:48.440 So Egypt led this mass campaign against schistosomiasis. 205 00:09:48.450 --> 00:09:53.220 However, did not sterilize the needles completely 206 00:09:53.220 --> 00:09:57.840 and this campaign unfortunately led to the spread 207 00:09:57.840 --> 00:10:00.510 of hepatitis C virus when blood 208 00:10:00.510 --> 00:10:03.360 from infected persons contaminated the needles 209 00:10:03.360 --> 00:10:06.810 that were then used to vaccinate other people 210 00:10:06.810 --> 00:10:08.403 against schistosomiasis. 211 00:10:10.350 --> 00:10:11.460 So as I just mentioned, 212 00:10:11.460 --> 00:10:14.460 the areas that have the highest rates 213 00:10:14.460 --> 00:10:16.980 of hepatitis C virus are spread around the world. 214 00:10:16.980 --> 00:10:18.840 So there's some South American countries, 215 00:10:18.840 --> 00:10:20.010 some African countries 216 00:10:20.010 --> 00:10:24.210 and some East Asian countries that have high burdens 217 00:10:24.210 --> 00:10:25.593 of hepatitis C virus. 218 00:10:26.910 --> 00:10:28.710 We also see that approximately 30% 219 00:10:28.710 --> 00:10:31.620 of HIV infected patients in the US are also infected 220 00:10:31.620 --> 00:10:33.360 with hepatitis C virus. 221 00:10:33.360 --> 00:10:36.630 HIV and HCV co-infection is due 222 00:10:36.630 --> 00:10:40.320 to blood-borne transmission of both viruses with IV drug use 223 00:10:40.320 --> 00:10:43.350 and/or unprotected sex with multiple partners. 224 00:10:43.350 --> 00:10:45.960 Survival has improved for HIV-infected individuals due 225 00:10:45.960 --> 00:10:48.780 to highly active antiretroviral therapy. 226 00:10:48.780 --> 00:10:51.390 But nevertheless, patients coinfected with HIV 227 00:10:51.390 --> 00:10:54.840 and HCV have more rapid progression of liver cirrhosis 228 00:10:54.840 --> 00:10:56.760 and are at increased risk of liver failure 229 00:10:56.760 --> 00:10:59.640 and hepatocellular carcinoma compared to those infected 230 00:10:59.640 --> 00:11:00.637 by only HCV. 231 00:11:02.022 --> 00:11:04.770 Hepatocellular carcinoma has become the leading cause 232 00:11:04.770 --> 00:11:08.133 of non AIDS-related death among co-infected individuals. 233 00:11:09.240 --> 00:11:11.430 We also see that aflatoxins 234 00:11:11.430 --> 00:11:13.470 or mycotoxins produced by certain species 235 00:11:13.470 --> 00:11:15.450 of fungus are a key risk factor 236 00:11:15.450 --> 00:11:17.223 for hepatocellular carcinoma. 237 00:11:18.270 --> 00:11:21.360 So these fungi readily colonizing contaminated grain 238 00:11:21.360 --> 00:11:24.300 before harvest, and during storage 239 00:11:24.300 --> 00:11:26.940 in areas and times of high humidity. 240 00:11:26.940 --> 00:11:28.560 We see this effects of wide variety 241 00:11:28.560 --> 00:11:32.010 of crops, including cereals, oil seeds, spices 242 00:11:32.010 --> 00:11:33.360 and tree nuts. 243 00:11:33.360 --> 00:11:35.460 Humans are primarily exposed to these toxins 244 00:11:35.460 --> 00:11:38.940 by consuming multi-grains and exposure rates are highest 245 00:11:38.940 --> 00:11:42.090 in populations with high rates of hepatocellular carcinoma, 246 00:11:42.090 --> 00:11:44.340 particularly in the nations of sub-Saharan Africa 247 00:11:44.340 --> 00:11:46.490 and in certain provinces of southern China. 248 00:11:48.840 --> 00:11:51.120 Other risk factors for hepatocellular carcinoma, 249 00:11:51.120 --> 00:11:55.260 include chronic alcohol consumption, which leads 250 00:11:55.260 --> 00:11:57.030 to a replacement of necrotic liver tissue 251 00:11:57.030 --> 00:12:01.593 by fibrosis and severe alcoholic liver cirrhosis. 252 00:12:05.670 --> 00:12:07.560 So we see that when looking 253 00:12:07.560 --> 00:12:10.360 at the progression of non-alcoholic fatty liver disease, 254 00:12:11.598 --> 00:12:16.598 this disease first becomes non-alcoholic steatohepatitis 255 00:12:17.700 --> 00:12:22.700 or NASH, then continues onto fibrosis and finally, resulting 256 00:12:22.770 --> 00:12:25.770 in cirrhosis, which as previously mentioned, 257 00:12:25.770 --> 00:12:29.823 leads to an elevated risk of hepatocellular carcinoma. 258 00:12:31.440 --> 00:12:32.670 So we also see 259 00:12:32.670 --> 00:12:34.770 that there are some inherited genetic disorders related 260 00:12:34.770 --> 00:12:36.540 to hepatocellular carcinoma risk: 261 00:12:36.540 --> 00:12:39.930 cigarette smoking, obesity, other comorbidities, 262 00:12:39.930 --> 00:12:42.990 as well as exposure to vinyl chloride, 263 00:12:42.990 --> 00:12:45.570 which is a compound used in the plastics industry. 264 00:12:45.570 --> 00:12:46.710 This can cause a rare form 265 00:12:46.710 --> 00:12:49.740 of liver cancer called hepatic angiosarcoma 266 00:12:49.740 --> 00:12:51.783 that appears many years after exposure. 267 00:12:53.730 --> 00:12:58.730 Finally, turning to cholangiocarcinoma. 268 00:12:58.860 --> 00:13:01.470 It is an uncommon malignancy. 269 00:13:01.470 --> 00:13:03.390 It affects the epithelial lining of the gallbladder 270 00:13:03.390 --> 00:13:06.840 or bile ducts, and it's an intrahepatic disease, 271 00:13:06.840 --> 00:13:09.660 which affects the gallbladder and ducts within the liver. 272 00:13:09.660 --> 00:13:12.330 It also can cause an extra hepatic disease 273 00:13:12.330 --> 00:13:14.520 affecting the biliary ducts outside the liver. 274 00:13:14.520 --> 00:13:17.640 So really we see these two manifestations. 275 00:13:17.640 --> 00:13:21.303 Though it's important to note that this is uncommon. 276 00:13:22.410 --> 00:13:24.540 When we're looking at the global epidemiology 277 00:13:24.540 --> 00:13:26.703 of cholangiocarcinoma, we see 278 00:13:26.703 --> 00:13:29.400 it's a relatively rare malignancy 279 00:13:29.400 --> 00:13:30.960 but the incidence is highest 280 00:13:30.960 --> 00:13:33.060 in certain regions of Southeast Asia. 281 00:13:33.060 --> 00:13:36.120 That's attributable to endemic liver parasites there. 282 00:13:36.120 --> 00:13:39.510 The annual incidence in Northern Thailand is 135 283 00:13:39.510 --> 00:13:42.810 per 100,000 in men, and 43 per 100,000 284 00:13:42.810 --> 00:13:46.770 in women compared to only one to two cases per 100,000 285 00:13:46.770 --> 00:13:47.763 in the US. 286 00:13:49.470 --> 00:13:52.650 We also see that mortality rates 287 00:13:52.650 --> 00:13:55.410 largely mirror incidence rates, 288 00:13:55.410 --> 00:13:58.290 especially in areas where infection 289 00:13:58.290 --> 00:14:00.900 with liver flukes are common. 290 00:14:00.900 --> 00:14:05.370 Risk factors for cholangiocarcinoma include gallstones, 291 00:14:05.370 --> 00:14:07.740 chronic alcohol abuse, hepatitis, cirrhosis, 292 00:14:07.740 --> 00:14:10.080 HIV infection, liver stones 293 00:14:10.080 --> 00:14:14.010 and congenital liver abnormalities. 294 00:14:14.010 --> 00:14:15.600 We also see that in high income countries, 295 00:14:15.600 --> 00:14:17.340 like the US, an important risk factor 296 00:14:17.340 --> 00:14:19.428 for the development of cholangiocarcinoma 297 00:14:19.428 --> 00:14:23.144 is the presence of primary sclerosing cholangitis, 298 00:14:23.144 --> 00:14:25.770 which is an inflammatory disease of the bile ducts 299 00:14:25.770 --> 00:14:28.413 that arises in patients with ulcerative colitis. 300 00:14:30.030 --> 00:14:31.530 Finally, it's important to note 301 00:14:31.530 --> 00:14:34.860 that the liver is the most common site of metastasis 302 00:14:34.860 --> 00:14:37.620 of primary malignancies at other anatomic sites. 303 00:14:37.620 --> 00:14:41.010 This is due to the hepatic portal system of blood flow 304 00:14:41.010 --> 00:14:46.010 and these other malignancies largely 305 00:14:47.760 --> 00:14:49.050 have poor survival rates 306 00:14:49.050 --> 00:14:51.603 when they metastasize to the liver.