Why am I so darn tired?

Clinical pearls for frontline PCPs

A 75-year-old man presents for evaluation of profound fatigue of at least 3 months’ duration.

He denies fevers, chills, sweats, unusual rashes or lumps. He has lost about 8 lbs in the past 6 months despite a reasonably good appetite. He denies cough, shortness of breath or chest pain. He has not had any nausea, vomiting, abdominal pain or change in bowel habits.

His past medical history shows no significant illnesses. He has not seen a physician for over 10 years. The patient is taking no medications.

Philip A. Bain

The medical assistant checks him in. His BP is 140/90, his heart rate is 80 and his weight is 190 lbs.

She presents his case to the physician:

“Doc, this 75-year-old man is here to see why he is so tired. He has been fatigued for at least 3 months. He has lost 8 lbs in the past 6 months or so, and his belt is two notches looser. He has not been to a doctor in over 10 years. If you ask me, he looks pale as a ghost.”

The physician enters the room, and the first thing that jumps out at her is the patient’s pallorous appearance. His conjunctivae are very pale. She asks if he has had any odd food cravings lately. The patient thought that this was a very unusual question but says, “come to think of it, I have really been eating a lot of ice lately. I must have four or five glasses of ice every day. Weird, huh?"

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The physical exam is normal other than the pallor. The physician performs a rectal exam, and although the prostate felt perfectly normal, the stool is quite dark and was hemoccult positive. He denies any change in his bowel pattern, specifically no melena, hematochezia, bloating, constipation or change in stool caliber. She orders labs, and they are as follows:

• White blood cell count: 7.2 with a normal shift
• Hematocrit (HCT): 20.1
• Mean corpuscular volume (MCV): 65
• Platelet count: 185,000
• Complete metabolic panel (CMP): normal
• Thyroid stimulating hormone (TSH): normal

She asks the lab to add on iron studies and a reticulocyte count, and these return with the following results:

• Iron: 20
• Total iron binding capacity (TIBC): 400
• Ferritin: 30
• Reticulocyte count: 1.5%, with a calculated reticulocyte production index of 1.5

The physician considers ordering a celiac panel but decides against it given the strongly positive hemoccult test. She sets him up for an upper and lower endoscopy and starts him on ferrous sulfate (FeSO4) 325 mg daily.

At his follow-up office visit, the physician reviews the upper endoscopy, which shows mild gastritis. The small bowel looks normal without blunted villi. The colonoscopy has an important finding of a large circumferential apple core-like mass in the ascending colon. Biopsy shows adenocarcinoma of the colon without extension to the adjacent lymph nodes. Follow-up blood work shows an HCT of 23 with an MCV of 68 and ferritin of 40. She adds on a carcinoembryonic antigen (CEA), and this returns 8.0. Arrangements are made for the patient to see a local surgeon. He ultimately undergoes a preoperative abdominal, pelvic and chest CT, and these are negative for metastatic lesions. He undergoes a laparoscopic right hemicolectomy. The pathology shows a 4 cm colon lesion — adenocarcinoma — stage II colon cancer with clear margins. Post-op CEA is 2.0. He is referred to a local oncologist who does not recommend any adjuvant chemotherapy but does request a follow-up CEA and colonoscopy to be repeated in 6 months.

Lessons learned

1. Anemia is very common — up to one-third of the global population has some type of anemia. Anemias are usually classified by the red cell size: microcytic (MCV less than 80), normocytic (MCV 81 to 99) and macrocytic (MCV greater than 99). We will discuss microcytic anemias only in this article and visit macrocytic and normocytic anemias in future articles.
2. The main causes of microcytic anemia (MCV less than 80) are iron deficiency, bleeding — gastrointestinal (GI), menstrual, epistaxis, etc. — thalassemia, anemia of chronic disease and increased iron demand such as with pregnancy. The causes of iron deficiency include bleeding, frequent blood donations, celiac disease, malabsorption and poor dietary intake of iron. Patients can have iron deficiency without anemia and, although somewhat controversial, treatment with iron in the absence of anemia may help some symptoms like fatigue.
3. Key features of a history of microcytic anemia include the acuity of onset, presence of relevant comorbid conditions, weight loss, fatigue and weakness. The patient should be asked about exercise tolerance, shortness of breath, syncope and the presence of chest pain. If the patient is female who has menstrual periods, she should be asked about menorrhagia. In men, the cause is GI bleeding until proven otherwise. PCPs should ask about the patient’s bowel patterns, specifically about melena, hematochezia, constipation and change in stool caliber. The patient should be asked about other signs of obvious bleeding and bruising.
4. The physical exam may be notable for normal vital signs, but hypotension, tachycardia and tachypnea may be present.
5. Signs may include generalized pallor and conjunctival and nail bed pallor.
6. Initial evaluation should include a complete blood count with hemoglobin (HGB) and MCV, as well as reticulocyte count, TSH and CMP. If MCV is less than 80, iron studies — eg, iron, TIBC and ferritin — should be done. Typically, anemia of iron deficiency has a low iron, a high TIBC and a low ferritin. Anemia of chronic disease, including chronic inflammation, often shows a low iron, a low TIBC and a high ferritin (see Table). Ferritin can be an acute-phase reactant and may be falsely elevated if significant inflammation is present.
7. The reticulocyte count should be checked, and the reticulocyte production index (RPI) should be calculated using one of the common medical calculators that ask for HGB and reticulocyte count (RPI = HCT/45 × reticulocyte count/maturation, with maturation = 1.0 for HCT 40%; 1.5 for HCT 30%-39.9%; 2.0 for HCT 20%-29.9%; and 2.5 for HCT < 20%).
8. An RPI greater than 3 represents a normal marrow response to anemia — a hyperproliferative response (eg, hemolysis). An RPI of less than 2 suggests an inadequate response to anemia — a hypoproliferative response (eg, bone marrow infiltration).
9. Iron deficiency in a patient older than 40 years of age without symptoms suggestive of an obvious bleeding source should prompt consideration of GI bleed, especially a right-sided colon cancer. The reason that right-sided colon cancers can present late is because stool is thin and fluidlike in the right colon, which can pass by a large right-sided colon mass without symptoms.
10. Pica refers to a peculiar manifestation of iron deficiency anemia and is described as unusual cravings for items that are not food and/or have no nutritional value like ice, dirt and clay.
11. An unusual cause of very low MCV can be a thalassemia. These are disorders of abnormal hemoglobin — either alpha or beta globin. The MCV is usually profoundly low for the relative normal HCT. For example, a patient with HCT of 36% with an MCV of 65 should prompt consideration of a thalassemia. People with thalassemia can range from having normal hemoglobin to profound anemia. This may be one of the rare times that the red blood count can be helpful as thalassemias often have a higher-than-normal RBC. The patient’s ancestry may provide a clue regarding thalassemias. Alpha thalassemia is highly prevalent in Southern China, Malaysia and Thailand. Mild forms of alpha thalassemia are commonly seen in patients from Africa. Beta thalassemia is prevalent in Africa.
12. For iron repletion, oral FeSO4 325 mg daily is prescribed. It should be given on an empty stomach, and the patient should be warned that it can cause melenic (black) stools. Typically, 3 to 6 months of oral iron are required to replete iron stores and normalize ferritin levels. If iron needs to be replaced urgently, if the patient has upper GI bleeding leading to the iron deficiency or when oral iron is not absorbed normally, IV iron may be needed.

References:

• Chaudhry HS, Kasarla MR. Microcytic hypochromic anemia. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470252/.
• DeLoughery TG. N Engl J Med. 2014;doi:10.1056/NEJMra1215361.
• Ganesan PR, Vasauskas AA. Cureus. 2023;doi: 10.7759/cureus.37904.