Transcript

	It was another fine day in the surgical ward. Doctor Lee, the consultant surgeon, was carrying his daily rounds. He had completed the rounds of the general ward, and had now come to see his private ward cases. Doctor Sam, the houseman, was presenting the case.
Sam	This is a patient with hepatocellular cancer and colon cancer.
	Doctor Lee raised his eyebrows with interest.
Sam	He is a 53-year-old bank manager. He has been feeling tired lately, so he went to his GP for a check. The GP ordered some tests, and found an elevated AFP and CEA.
Dr Lee	What’s the history?
Sam	Well, he’s been feeling tired for the last two weeks. It all seemed to start with a runny nose and cough. This lasted for three to four days, then it resolved. He went to his GP who said it was a viral infection, and no antibiotics were required. The rhinitis and cough stopped after four days, but he kept feeling tired, so he went to his GP again. The GP sent some tests, and found that the serum AFP and CEA levels were high, so he referred the patient here. Incidentally, the patient has a long history of alcohol abuse.
Dr Lee	How much alcohol abuse?
Sam	He claimed to take five cans of beer daily, and has been doing this for the last twenty years.
Dr Lee	Have you examined him?
Sam	Yes. He is afebrile. General physical examination is unremarkable. There’s no lymphadenopathy, and the throat is clear. The chest also seems to be clear, but on examination of the abdomen he has a little ascites.
Dr Lee	Let me check…(pause as he checks) Yes, you are quite right, he does have ascites.
	Doctor Lee stepped back, then asked.
Dr Lee	Anything else?
Sam	He has a little loss of appetite as well. There are no features of liver cell failure. The urine colour is normal. There is no fever now. The patient has a past history of hospitalization due to motor vehicle accident secondary to alcohol intoxication, leading to a humeral fracture. There is no significant family history; no history of any malignancy. (short pause) He smokes 10 cigarettes per day.
Dr Lee	So… alcohol dependence with elevated AFP and CEA and ascites. What are the values?
Sam	AFP of 11ng/ml and CEA of 30ng/ml.
Dr Lee	What is your diagnosis?
Sam	(defensively like a slightly unsure houseman) His AFP and CEA are both raised. He feels lethargic and he’s got ascites. So my diagnosis is hepatocellular cancer with concurrent colorectal cancer… (short pause) and peritoneal metastases.
Dr Lee	What are your plans?
Sam	I’ve ordered liver function tests, and ultrasound of the abdomen today. I have also arranged a colonoscopy for tomorrow morning.
Dr Lee	I see. You don’t think that this is a colorectal cancer that has metastasized to the liver?
Sam	I don’t think so. CRC metastasis in the liver should not raise the AFP. So I think this is a patient with two primary cancers, one in the liver, another in the colon.
Dr Lee	I see your point. Did you find an enlarged liver?
Sam	No. But I think he may have alcohol-related chronic liver disease. This would have shrunk the liver, so in a hepatoma the liver may not be enlarged.
Dr Lee	You are right. But if the liver has shrunk due to chronic liver disease, wouldn’t you expect to also find an enlarged spleen?
Sam	Errr… yes, I guess.
Dr Lee	Would you like to examine his abdomen again for a spleen?
	The houseman did so. As she did, she frowned a little.
Sam	Yes, the spleen is palpable! I missed it.
Dr Lee	So now what do you think?
Sam	(a little excited, triumphant) I think that confirms the diagnosis. Cirrhosis is a risk factor for hepatocellular cancer. He has HCC developing as a complication of the cirrhosis and he has colon cancer.
Dr Lee	(Thoughtfully) Alright. I agree that an ultrasound and colonoscopy should be carried out in a 53-year-old man with ascites and an elevated AFP and CEA. Then, let’s proceed with your investigations. We’ll discuss when the results are out.
Sam	The team went to the next private room. Turning back, he looked at the patient, then the houseman, and smiled.
Dr Lee	I guess we’ll have an interesting discussion tomorrow.
	The next day, Doctor Lee started his round. He was interested to learn what the ultrasound and the colonoscopy showed, but more importantly, the lesson the houseman was going to learn.
Dr Lee	So…this is the patient with the raised AFP and CEA. What are the results?
Sam	(sounding confused) The… the abdominal ultrasound showed no masses or any signs suggestive of malignancy. But the liver is consistent with cirrhosis. The spleen is enlarged, and there is mild-moderate ascites.
Dr Lee	Okay… And what about the colonoscopy?
Sam	(Hesitantly) Well, the colonoscopy…
Dr Lee	Let me guess….negative?
Sam	Yes…it came back to be negative.
Dr Lee	I thought it might.
Sam	I think we should do a CT.
Dr Lee	How about considering the possibility that the patient has no malignancy?
Sam	But if there are no malignancies, then why is the AFP and CEA raised in this patient?
	The houseman frowned, appearing to be confused.
Dr Lee	Now, AFP is a glycoprotein that is produced since we are embryos. The synthesis is initially from the yolk sac and liver, but becomes predominantly liver 1-2 months after delivery.(1) Now tell me, what is cirrhosis of the liver?
Sam	Severe fibrosis of the liver?
Dr Lee	That’s right. Now, fibrosis is a type of healing mechanism when the liver sustains an insult, like alcohol. AFP then plays an important role in the regeneration of liver tissues. In hepatocellular carcinoma, the increased cellular division increases the AFP.  In chronic liver disease, where there is inflammation, regeneration takes place, replacing the cells with scar tissues leading to cirrhosis. Therefore, chronic liver disease is also associated with the rise in AFP level.(2)
Sam	And I guess the ascites is because of cirrhosis? Oh, I see! The upper respiratory infection caused the liver to decompensate!
Dr Lee	Exactly. Any intercurrent infection can cause a cirrhotic liver to decompensate. That’s why he has ascites. Your liver function tests will probably show an elevated bilirubin, though he is not clinically icteric.
Sam	Yes, they do. But what about the high CEA level?
Dr Lee	Do you know that CEA is also raised in patients with chronic liver disease? CEA is released during the regeneration of damaged liver cells as well. Moreover, the main excretion pathway of CEA is via liver metabolism.(3) With the damaged liver…
Sam	There is a decrease in the uptake of CEA and thus the elevated serum CEA level!!!
Dr Lee	Now you got it! Remember, although CEA and AFP are tumour markers, they are not pathognomonic. A raised level of either CEA or AFP doesn’t confirm the diagnosis, and there is a need to combine it with the history and other modalities, such as ultrasound.(4) You should also note that an elevation in AFP should be more than 400ng/ml (2) and CEA of over 40ng/ml (3) to be confirmatory of the presence of cancers.
Sam	Ah…now I understand.

References

1. Tomasi TB. Structure and Function of Alpha-Fetoprotein. Annu Rev Med. 1977 Feb 1;28(1):453–65.

2. Liu Y, Lin B, Zeng D, Zhu Y, Chen J, Zheng Q, et al. Alpha-fetoprotein level as a biomarker of liver fibrosis status: a cross-sectional study of 619 consecutive patients with chronic hepatitis B. BMC Gastroenterol. 2014 Aug 16;14:145–145.

3. Bullen AW, Losowsky MS, Carter S, Patel S, Neville AM. Diagnostic Usefulness of Plasma Carcinoembryonic Antigen Levels in Acute and Chronic Liver Disease. Gastroenterology. 1977 Oct 1;73(4):673–8.

4. Chang T, Wu Y, Tung S, Wei K, Hsieh Y, Huang H, et al. Alpha-Fetoprotein Measurement Benefits Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis. Am J Gastroenterol. 2015 Jun;110(6):836–44.