Clinical Biochemistry (PHB433) Lecture 9 PDF

Biochemistry Department Clinical Biochemistry (PHB433) Nora Aborehab, PhD Assoc. Prof. of Biochemistry & Molecular Biology Faculty of Pharmacy MSA University  References 1. Clinical chemistry : principles, techniques, and correlations/Michael L. Bis...

Biochemistry Department Clinical Biochemistry (PHB433) Nora Aborehab, PhD Assoc. Prof. of Biochemistry & Molecular Biology Faculty of Pharmacy MSA University  References 1. Clinical chemistry : principles, techniques, and correlations/Michael L. Bishop, Edward P. Fody, Larry E. Schoeff.-7th ed. 2. Lecture notes: Clinical biochemistry/Simon Walker, Geoffrey Beckett, Peter Rae, Peter Ashby- 9th ed. Interactive teaching methods & activities Case study through group work  Objective of thelecture: By the end of the lecture, the student will be able to 1 Illustrate causes of cancer 2Determine the properties, clinical importance and types of tumor markers  Tumor (Neoplasm) It is an abnormal mass of cells that have no useful function & grows in an uncontrolled manner at the expense of healthy tissues. Types of Tumor  Benign tumors.  Malignant tumors. Benign tumor cells: are characterized by 3 properties: 1- Diminished control of growth. 2-Do not invade local tissues. 3-Do not spread to the other parts of the body. Malignant tumor cells (cancer cells): are characterized by 3 properties: 1- Diminished control of growth. 2- Invasion of local tissues. 3- Spread (metastasis) to the other parts of the body.  Causes of cancer Radiation energy Chemical compounds Oncogenes  1- Radiation energy  They cause cancer through: i. Direct effects on DNA causing DNA damage leading to cancer formation. ii. Formation of free radical. e.g. superoxide causing DNA damage leading to Cancer formation.  Examples: ultraviolet rays, x-rays and γ- rays.  2- Chemical compounds a) Pollution. b) Occupational hazards: e.g. benzene and asbestos. c) Diet: Alfatoxin B1, which is produced by the mold Aspergillus flavus and sometimes food. d) Bad Lifestyle e.g. cigarette smoking  3- Oncogenes a) These are abnormal genes. b) They are mutant (altered) proto-oncogenes. c) They can lead to malignant tumors.  Two classes of genes have been discovered that function in neoplastic transformation: 1-Oncogenes: Which are genes that promote development of cancer (tumors). Their names are derived from the Greek word (onkos) which means bulk or mass. 2-Tumor suppressor gene: Which are genes that suppress the development of cancer (tumors).  Mechanism of action of oncogenes Proto-oncogenes are genes coding for proteins involved in controlling cell growth e.g. growth factors and receptors for growth factors. Oncogenes arise from pre-existing normal genes (proto-oncogenes). They only become oncogenes if their sequences have been altered by mutation.  As a result of that alteration, cells synthesize proteins that are abnormal in structure and function. If the control of oncogene expression by tumor suppressor genes is also disturbed, transformation and unregulated proliferation of the cells can occur.  Cancer Staging  Cancer staging is the process of determining the extent to which a cancer has developed by spreading.  The stage generally takes into account the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes it has spread to (if any), and whether it has appeared in more distant locations (metastasized). Cancer Staging & progression Tumor markers  1- Definition  They are biological substances synthesized and released by cancer cells; or produced by the host cells in response to the presence of cancerous tissue. 2- Site  They may be present in circulation, in body fluids or associated with cells: in the cytoplasm or on cell membrane. 3- Properties of ideal tumor markers A- Have high disease sensitivity i.e. it should be positive in all patients with particular cancer. False negative is a malignant case which gives a normal value for the marker whereas it is proved malignant histopathologically. Cut-off value is the highest value obtained by the normal control. 3- Properties of ideal tumor markers B- Have high disease specificity i.e. it should be negative in all normal population. False positive is a normal case with elevated marker level above the cut-off value. C- Its level reflects the stage of the disease. D- Its level must be stable i.e. not subjected to marked fluctuation in stable disease state. E- Organ specific i.e. positive only in certain organ tumor. 4- Clinical importance of ideal tumor marke r - Ideally, tumor marker should provide the following uses in patients having cancer: A- Diagnosis: screening for the presence of malignancy through symptomatic patients and differentiating malignant from benign conditions. B- Screening: the asymptomatic population. C- Staging: the disease, by defining extent of the diseases. D- Monitoring: the response of the therapy. E- Assessing prognosis: help to assess how aggressive a cancer is likely to be or even how well it might respond to certain drugs. F- Detecting recurrence: Markers are used to detect cancers that recur after initial treatment. 5- Classification of tumor markers Hormones Enzymes Tumorantigens  A- Hormones A. Eutopic:  Insulin production by islet cell tumor.  Calcitonin production by medullary thyroid carcinoma. B. Ectopic:  The production of ACTH, ADH and calcitonin by carcinoma of the lung.  Parathyroid hormone by renal cancer.  B- Enzymes  Example of enzymes that are used as tumor markers are: Alkaline phosphatase (ALP) in liver, bone and GIT cancer,  Prostatic acid phosphatase (PAP)  Prostate-specific antigen (PSA)  C- Tumor antigen 1- Oncofetal antigens: a) These are proteins produced normally during fetal life. They are present in high concentration in the serum of fetus and decrease to low levels or disappear after birth. In cancer patients, these proteins re-appear. b)The production of these proteins demonstrates that certain genes are reactivated as the result of the malignant transformation of cells. c)They include Carcinoembryonic antigen (CEA) in colorectal cancer, breast and lung cancers, and α- Fetoprotein (AFP) in hepatocellular carcinoma.  C- Tumor antigen 2- Other tumor antigens: a)Carbohydrate antigen 19.9 (CA 19.9) in gastric, pancreatic and colorectal cancer. b) Cancer antigen 125 (CA 125) in Ovariancancer. c) Cancer antigen 15.3 (CA 15.3) in breastcancer. d) Cancer antigen 50 (CA 50) in pancreaticcancer. e)Tissue polypeptide antigen (TPA) in breast and bladder cancer. 3- Proteins: a) B2 macroglobulin in lymphoma & multiple myeloma. Malignant disease where tumour markers are used in clinical practice. Tumour markers commonly used in clinical practice 1 Carcinoembryonic antigen (CEA) CEA is a highmolecular weight glycoprotein The most widely used marker to diagnose, and monitor patients withcolorectal cancer. CEA levels should return to normalpost‐operatively following successful surgical resection. A rise in CEA level after surgical resection of tumors suggests residual or metastatic disease. Serial monitoring with CEA can detect recurrent disease Carcinoembryonic antigen (CEA) levels in a patient who presented with a colonic tumour.  α‐Foetoprotein (AFP) Patients with cirrhosis and persistent infection with hepatitis B and C are at high risk of developing hepatocellular carcinoma. Measurement of serum AFP on a regular basis (every 6–12 months) appears to be of value to allow early detection of tumour. Serum AFP is increased in many patients with cirrhosis, but a concentration in excess of 400 kU/L is almost diagnostic of malignancy. Serum AFP is of value both for monitoring response to treatment and potential recurrence. Measurement of serum AFP is also important in the investigation of patients presenting with potential germ‐cell tumours. AFP concentrations are greatly increased during pregnancy, or in neonates and infants.  CA‐125 CA‐125 is a high molecular weight glycoprotein Has role in the screening and monitoring of ovarian carcinoma. Serum CA‐125 is elevated when there is vascular invasion, tissue destruction and inflammation associated with malignancy. It is increased in over 90% of women with advanced ovarian cancer disease. CA‐125 can also be increased during menstruation and pregnancy and in other nonmalignant conditions such as endometriosis, peritonitis and cirrhosis. Up to a third of patients with ovarian cancer will not demonstrate elevated CA‐125.  Investigation of suspected ovarian cancer Persistent or frequent (>12 times per month) symptoms requiring investigation with CA‐125 Abdominal bloating/distension Pelvic pain Unexplained weight loss Fatigue Loss of appetite or early satiety Increased urinary urgency or frequency. 50 years of age or over with IBS–like symptoms If CA‐125 is >35 kU/L, calculate the risk of malignancy index (RMI) RMI = U × M × CA‐125 U is the ultrasound score (0–5) M is menopausal status score: 1 = pre‐menopausal; 3 = post‐menopausal CA‐125 is serum concentration in kU/L If RMI >250, refer patient for specialist investigation  Prostate‐specific antigen (PSA) PSA is a glycoprotein used as a tumour marker to aid diagnosis and to monitor patients with prostatic cancer. PSA is detectable in the serum of healthy men and the concentration rises with age. Age-specific PSA reference range Elevated PSA levels are obtained in men with benign prostate hypertrophy (BPH) and prostate cancer. It was estimated that BPH tissue contributes 0.3ngPSA/gm of tissue, in contrast, prostate cancer tissue contributes about 10-fold more PSA.  Prostatic acid phosphatase (PAP) Prostatic acid phosphatase is a tumor marker of prostate cancer. PAP determination in conjunction with PSA measurements is useful in assessing the prognosis of prostate cancer. PAP is more specific than PSA and less false- positives are seen due to benign prostatic hyperplasia.  Prostate cancer Prostate cancer is the development of cancer in the prostate, a gland in the male reproductive system. The risk of prostate cancer increases with age with about 6 cases in 10 are diagnosed in men aged 65 or older, and it is rare before age 40. The average age at the time of diagnosis is about 66. Metastasis is the medical term for cancer that has been spread beyond the place where it started; where prostate cancer spreads to bones, also it is common to spread to liver or lungs.  Prostate cancer Signs and symptoms of prostate cancer: Early prostate cancer usually has no clear symptoms. Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hyperplasia These include frequent urination, nocturia (increased urination at night), difficulty starting and maintaining a steady stream of urine, hematuria (blood in the urine), and dysuria (painful urination). Most of the patients are diagnosed with one or more symptom  CA 19‐9 Measurement of CA 19‐9 is indicated in the post‐operative monitoring of patients with pancreatic tumors CA19-9 values can also be increased in patients with colorectal or other GI malignancies. Monitoring CA 19‐9 may also be useful in patients with primary sclerosing cholangitis. Patients with sclerosing cholangitis condition who subsequently develop cholangiocarcinoma often show a rapid rise in CA 19‐9 concentration to greatly elevated values.  Tumor marker guide Breast Prostate Cancer antigen 15.3 (CA 15.3) Prostatic specific antigen (PSA) Carcinoembryonic antigen (CEA) Prostatic acid phosphatase (PAP) Ovary Uterus Cancer antigen 125 (CA 125) Carcinoembryonic antigen (CEA) Carcinoembryonic antigen (CEA) Cancer antigen 125 (CA 125) Liver Testes Alpha Fetoprotein (AFP) Alpha Fetoprotein (AFP) Human chorionic gonadotropin (HCG) Pancreas Stomach Cancer antigen 50 (CA 50) Carcinoembryonic antigen (CEA) Cancer antigen 19.9 (CA 19.9) Cancer antigen 72.4 (CA 72.4) Lung Thyroid Carcinoembryonic antigen (CEA) Calcitonin Neron specific enolase (NSE) Carcinoembryonic antigen (CEA) Colorectum Urinary bladder Carcinoembryonic antigen (CEA) Carcinoembryonic antigen (CEA) Cancer antigen 19.9 (CA 19.9) Tissue polypeptide antigen (TPA) Lymphoma Leukemia Lactate dehydrogenase (LDH) Lactate dehydrogenase (LDH) B2-Microglobulin B2-Microglobulin Nonmalignant conditions that may cause increases in serum tumour markers.  Case 1 A 73‐year‐old man presented to his doctor, complaining of back pain and increasing problems with passing urin e. The following results from chemical tests were obtained: What is the likely diagnosis? Comments: The man is likely to have metastatic prostaticcancer. Although there is overlap in the levels of PSA seen in men with benign prostatic hypertrophy and those with prostatic cancer, the high levels of PSA found in this patient are usually seen only in patients with metastatic disease. The elevated ALP in the presence of normal GGT andother liver function tests also suggests metastatic spread tobone.  Case 2 A 50‐year‐old male lecturer presented to his doctor, complaining of tiredness, abdominal discomfort and poor appetite. He had worked in Africa in the past, where he had contracted hepatitis B and had become a carrier. On examination, he was jaundiced and his liver was enlarged. Urine was positive for both bilirubin and urobilinogen. What is the likely diagnosis? Comments: The patient has a primary hepatocellular carcinoma. This is a common in China, South‐East Asia and parts of Africa as a result of the high incidence of hepatitis B in these regions. Chronic carriers of the virus have an increased risk of developing the malignancy. The liver function tests show a mixed pattern of cholestasis, probably arising from the tumour, and hepatitis. The very high concentration of AFP is highly suggestive of hepatocellular carcinoma, but levels of up to ~400 kU/L can be found in some patients with nonmalignant hepatobiliary disease.  Extra readings Extra readings are recommended for types of breast cancer, lung cancer and colon cancer in the following links: https://www.cancer.org/cancer/types/breast- cancer/about/types-of-breast-cancer.html https://www.lung.org/lung-health-diseases/lung- disease-lookup/lung-cancer/basics/lung-cancer-types https://www.mskcc.org/cancer- care/types/colon/types Faculty of Pharmacy