3.4 Colorectal Neoplasms & Nutritional Deficiencies

Colorectal Neoplasms & Nutritional Deficiencies

Colorectal cancer is a leading cause of cancer mortality, and understanding screening recommendations and hereditary cancer syndromes is high-yield for the PANCE. Additionally, clinicians must recognize the classic clinical presentations, physical exam findings, and management of major vitamin deficiencies.

Colorectal Cancer Pathophysiology and Screening Guidelines

Colorectal cancer (CRC) primarily develops through the adenoma-to-carcinoma sequence, a multi-step genetic pathway involving the sequential mutation of key genes. This classic sequence begins with the loss or mutation of the Adenomatous Polyposis Coli (APC) tumor suppressor gene, leading to hyperproliferative epithelium. Subsequent activation of the KRAS oncogene promotes adenoma growth, and final inactivation of the p53 tumor suppressor gene leads to invasive carcinoma. Screening reduces mortality by detecting and removing precancerous adenomas. For average-risk individuals, screening begins at age 45 and continues until age 75. Acceptable screening modalities include colonoscopy every 10 years (the gold standard, allowing for concurrent polypectomy), annual Fecal Immunochemical Test (FIT) or guaiac Fecal Occult Blood Test (gFOBT), multitarget stool DNA (FIT-DNA) every 3 years, or flexible sigmoidoscopy or CT colonography every 5 years. Any positive non-colonoscopy screening test must be followed by a diagnostic colonoscopy. For individuals with a first-degree relative diagnosed with CRC before age 60, screening begins at age 40 or 10 years younger than the youngest relative's diagnosis (whichever is earlier) using colonoscopy every 5 years.

Hereditary Colorectal Cancer Syndromes

Two classic autosomal dominant syndromes are heavily tested on the PANCE:

• Familial Adenomatous Polyposis (FAP): Caused by a germline mutation in the APC gene on chromosome 5q. It is characterized by the development of hundreds to thousands of adenomatous polyps throughout the colon starting in adolescence. There is a near 100% risk of progression to colorectal adenocarcinoma by age 40 if left untreated. Management requires annual sigmoidoscopy starting at age 10-12, followed by a prophylactic total colectomy (usually before age 20) with ileal pouch-anal anastomosis (IPAA).
• Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer - HNPCC): Caused by mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) leading to microsatellite instability. It accelerates progression from polyp to cancer (typically 1-2 years compared to 10 years in sporadic cases). Lynch syndrome is associated with an increased risk of colorectal cancer (often right-sided) and extra-colonic malignancies, most notably endometrial cancer (the most common extra-colonic cancer in females), ovarian, gastric, and urinary tract cancers. Surveillance requires colonoscopy every 1-2 years starting at age 20-25. The Amsterdam criteria diagnose Lynch syndrome: at least 3 relatives with Lynch-associated cancers across 2 generations, with 1 diagnosed before age 50.

Major Vitamin Deficiencies

Nutritional deficiencies present with distinct clinical syndromes:

• Vitamin A (Retinol): Essential for the visual cycle as a component of rhodopsin. Deficiency presents with night blindness (nyctalopia), dry eyes (xerophthalmia), Bitot spots (foamy keratin patches on the conjunctiva), follicular hyperkeratosis, and impaired immunity. Acute toxicity can present with pseudotumor cerebri (idiopathic intracranial hypertension) and hepatomegaly, while chronic toxicity causes dry skin and alopecia.
• Vitamin B1 (Thiamine): Serves as a cofactor for key cellular respiration enzymes including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase. Deficiencies are common in alcohol use disorder. Dry Beriberi presents with peripheral neuropathy and muscle wasting. Wet Beriberi presents with high-output heart failure, dilated cardiomyopathy, and edema. Wernicke Encephalopathy is an acute syndrome featuring a classic triad of ophthalmoplegia/nystagmus, ataxia, and confusion. Korsakoff Psychosis is an irreversible syndrome characterized by retrograde/anterograde amnesia and confabulation. Crucially, clinicians must administer thiamine before glucose in malnourished or alcoholic patients to avoid precipitously worsening Wernicke encephalopathy by depleting remaining thiamine reserves during glycolysis.
• Vitamin B3 (Niacin): Niacin is synthesized from tryptophan, a process requiring pyridoxine (B6). Deficiency causes Pellagra, characterized by the 4 Ds: Dermatitis (photosensitive Casal necklace), Diarrhea, Dementia, and Death. It occurs in corn-based diets, alcohol use, Hartnup disease, and carcinoid syndrome.
• Vitamin B12 (Cobalamin): Vitamin B12 binds to intrinsic factor (produced by gastric parietal cells) and is absorbed in the terminal ileum. Deficiency presents with megaloblastic anemia (with hypersegmented neutrophils), glossitis, and subacute combined degeneration of the spinal cord (causing loss of vibratory and position sense, paresthesias, and ataxia). It is caused by vegan diets, pernicious anemia, or terminal ileum resection. Lab work reveals elevated methylmalonic acid (MMA) and homocysteine levels, distinguishing it from folate deficiency which has normal MMA levels and lacks neurological symptoms.
• Vitamin C (Ascorbic acid): Acts as a cofactor for prolyl and lysyl hydroxylase in collagen synthesis. Without vitamin C, collagen lacks tensile strength. Deficiency leads to Scurvy, characterized by follicular hyperkeratosis, coiled ("corkscrew") hairs, perifollicular hemorrhages, petechiae, ecchymosis, bleeding and inflamed gums (gingivitis), hemarthrosis, and impaired wound healing.
• Vitamin D (Calciferol): Vitamin D undergoes 25-hydroxylation in the liver and 1-alpha-hydroxylation in the kidney to its active form, 1,25-dihydroxyvitamin D. Deficiency causes Rickets in children (delayed growth, bowlegs, rachitic rosary) and Osteomalacia in adults (bone pain, muscle weakness, pseudofractures/Looser zones).