DIFFERENTIAL DIAGNOSIS

DIFFERENTIAL DIAGNOSIS

When a patient presents to a healthcare provider, the purpose of employing differential diagnosis is to narrow an indefinite number of possible diagnoses to a finite scope of diagnoses that can be either confirmed or ruled out through observation, measurement, and treatment outcomes.

The process begins with identification of the problem through symptoms and signs of disease. Then, the provider must frame a problem-specific list of possible diagnoses. The provider uses risk factors, symptoms, physical findings and disease “fingerprints” to hypothesize and to rank causal diagnoses, and, finally, the provider prioritizes tests that have a very high probability of ruling out highly ranked possibilities. Diagnosis is confirmed through positive diagnostic findings and treatment response.

PATIENT PRESENTATION

Today’s case, Ms. R.N., is a 36 yo Caucasian female who presents in the ED with headache, fatigue, weakness, dizziness, dyspnea, and tachycardia. She is afebrile and denies chest pain and fecal blood. Assessment reveals that her oral mucosa is pink and moist, but her tongue appears smooth. Her conjunctiva are pale. She reports that she has been eating ice frequently, and she says she occasionally craves clay. She reports that she has had fatigue and weakness for several weeks, but it has increased significantly in the last 2-3 days.

IDENTIFY THE PROBLEM

The first step in differentiating all possible diagnoses from the hypothesized diagnoses begins with identifying the patient’s problem. 

Identifying the problem begins with the subjective therapeutic interview. The interview covers the present history of the illness and the characteristics of symptoms, including onset, duration, quality, and aggravating and relieving factors.

Our patient has been feeling a headache, dizziness, fatigue and weakness constantly over the past several weeks with a significant increase in symptoms over the past 2 to 3 days. She is currently feeling short of breath but not experiencing chest pain.

We consider what signs we can observe through direct assessment of the patient.

  1. Heartbeat is rapid.
  2. Temperature is normal.
  3. Tongue is smooth.
  4. Conjunctiva are pale.

Even at this early stage of our assessment, we consider diagnoses related to infection much less likely. If Ms. RN’s symptoms were caused by infection, she would likely have a fever prompted by pyrogenic cytokines and/or exogenous pyrogens (McCance & Huether, 2019, p. 480).

Our pursuit of hypothetical diagnoses extends to Ms. RN’s family, social, surgical and medical history.

Considering the symptoms of headache, fatigue, tachycardia and dyspnea, Ms. RN’s family history is significant.

  1. Her living maternal grandfather has had a stroke.
  2. Her deceased maternal grandmother had chronic fatigue.
  3. Her deceased father had myocardial infarction.
  4. Her living paternal grandmother and grandfather have COPD, but Ms. RN is not a smoker.
  5. Her living mother has hypertension and a history of abnormal bleeding as evidenced by postpartum hemorrhage requiring transfusion.

According Ms. RN’s reported social history, she doesn’t use drugs, and she limits alcohol consumption to 1-2 drinks per week.

Her only surgery has been a tonsillectomy way back in 1998.

Her medical history includes two types of abnormal bleeding: epistaxis and menorrhagia.

PROBLEM-SPECIFIC DIAGNOSIS

Based upon reported symptoms; family, social, surgical and medical history; and physical finding of signs that are risk factors or “fingerprints” of disease, the provider will frame a problem-specific list of possible diagnoses. The provider must first organize the range of possible diagnoses and narrow the field of diagnoses using pivotal points to create a patient-specific differential before exploring the patient-specific diagnoses using history and physical findings (Stern, Cifu, & Altkorn, 2014).

Possible diagnoses can be organized in clinically useful anatomical, systemic or physiologic subgroups. For example, Ms. RN’s presentation with tachycardia and dyspnea relates anatomically to the heart and lungs, and her headache and dizziness relate anatomically to the brain. These same symptoms point toward problems with the cardiovascular, pulmonary, nervous, and, possibly, endocrine systems. Physiologically, her symptoms point toward problems in the function of gas exchange.

Next, the provider must limit possible diagnoses using pivotal points to create a patient-specific differential. Pivotal points are “one of a pair of opposing descriptors that compare and contrast diagnoses, or clinical characteristics” (Stern, Cifu, & Altkorn, 2014). Pivotal points may be temporal (i.e. acute vs. chronic onset, or episodic), situational (i.e. at rest, depending on body position, or accompanying emotional stress), or pathogenic (i.e. physiologic vs. psychogenic, or one system or anatomical structure over another) (Berliner et al., 2016, p. 835). Our patient has an acute onset of symptoms that have worsened over the past few days. Her symptoms have been fairly constant with no relieving factors, and we have narrowed down the physiological causes to cardio-pulmonary structures, the endocrine system or some functional problem with gas exchange. 

This information is just part of the exploration of diagnoses. The provider must also consider risk factors, associated symptoms and physical findings of the exam to further narrow the field. One key tool in the exploration process is the “fingerprint” symptom set: one or more symptoms that almost always points to a particular diagnosis (Stern, Cifu, & Altkorn, 2014).

The exploration process concludes with ranking of the differential and selection of a leading hypothesis, a must not miss hypothesis and an active alternative hypothesis. The leading hypothesis usually takes a probabilistic approach. Probable diagnoses are the disorders that are more likely. Due to “fingerprint” symptoms, risk factors and physical findings, these diagnoses have the highest pretest probability even before further testing is done. Ms. RN has a “fingerprint” symptom set that includes pale conjunctiva and a craving for ice. The must-not-miss hypothesis takes the prognostic approach. These diagnoses, if unchecked, lead to the most serious health consequences. Since Ms. RN shows both signs of tachycardia and symptoms of dyspnea, cardio-pulmonary disorders must be ruled out even if a less serious condition is highly likely to be present. An active alternative hypothesis takes the pragmatic approach. Diagnoses in this category are very responsive to treatment and are quite easily ruled in or out by routine diagnostics (Stern, Cifu, & Altkorn, 2014).

Once a differential diagnosis has been ranked, the provider works with the patient to test the hypotheses. The provider prioritizes tests that have a very high likelihood of ruling in or ruling out the diseases under consideration. Results are used to isolate a diagnosis and create a treatment plan, and, often, to monitor a treatment response. In an ideal world, positive and negative results would correspond 100% to the presence or absence of disease (Stern, Cifu, & Altkorn, 2014). But that just isn’t so. False negatives and positives muddy the diagnostic picture. For this reason, diagnostic confirmation is made through a positive treatment response.

In the case of Ms. RN, the must-not-miss diagnosis is cardio-pulmonary in nature because prognosis is very poor if a serious problem is not detected. Following up on this concern makes sense because, though she has no chest pain, cardiac issues sometimes present atypically in women and silent ischemia is possible without pain (McCance & Huether, 2019, pp. 1080-1081). What’s more, nearly half of MIs are not preceded by any previous symptoms of pain (McCance & Huether, 2019, p. 1086). Testing is fairly non-invasive and highly reliable in ruling diagnoses in or out. The physician has reason to suspect cardio-pulmonary disorder because of Ms. RN’s family history of myocardial infarction in her deceased father. She has associated symptoms of dyspnea and dizziness, and a physical finding of tachycardia (McCance & Huether, 2019, p. 1190).

Diagnostic testing for a “silent” myocardial infarction or pulmonary embolism–the two most dangerous cardio-pulmonary diagnoses likely in the case of Ms. RN–includes pulse oximetry, cardiac troponin I (cTnI), blood glucose, 12-lead ECG, c-reactive protein (CRP), white blood cell count (McCance & Huether, 2019, p. 1086), and serum D-dimer (McCance & Huether, 2019, p. 1191).

Test results that follow, except pulse oximetry, are negative, confirming a very high likelihood that Ms. RN does not have a cardio-pulmonary issue such as MI or PE.

  • Pulse oximetry – low due to hypoxemia
  • Natriuretic peptides – normal – excludes congestive heart failure as a source of dyspnea with 94-98% accuracy (Berliner et al., 2016, pp. 836-837)
  • Blood glucose – normal – r/o MI which may cause elevated blood glucose
  • 12-lead ECG – normal – r/o MI in all four chambers of the heart and PE that may put a strain on the right side of the heart
  • Cardiac troponin I – normal – r/o MI and PE that may put strain on the heart
  • C-reactive protein and leukocytes – normal – indicating no acute inflammation
  • Serum D-dimer – negative – r/o presence of PE degradation

Ms. RN’s active alternative diagnosis is hyperthyroidism: the hypersecretion of thyroid hormone. Prevalence of hyperthyroidism is high in the United States at 1.3% (Leo, Lee, & Braverman, 2016). Although Ms. RN doesn’t have significant risk factors for hyperthyroidism, she reports associated symptoms of fatigue and dyspnea and assessment revealed the physical finding of tachycardia. Notably, Ms. RN is lacking the fingerprint symptoms for hyperthyroidism, exophthalmos with enlarged goiter. Hyperthyroidism may be also contraindicated because Ms. RN has heavy menstrual periods rather than scant or absent periods, and she doesn’t complain of GI hypermotility, heat intolerance, hair loss, or palmar erythema (McCance & Huether, 2019, p. 678).  

Thyroid trouble can be confirmed in more than 95% (Leo, Lee & Braverman, 2016) of cases by measuring blood levels of thyroid stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) (McCance & Huether, 2019, p. 676). If TSH values are normal, further testing is necessary to determine the etiology of the thyroid hormone hypersecretion. In this case, tests indicating thyroid abnormality are normal and hyperthyroidism is highly unlikely as the source of Ms. RN’s symptoms.

The leading hypothesis is that Ms. RN has anemia, a condition defined as hemoglobin level of less than 120 g/L in women (Lambert & Beris, 2009, p. 109), hematocrit of <37% (< 0.37), or RBC of <4 million/mcL (Braunstein, 2019). In the US, nine to twelve percent of non-Hispanic white women have anemia (Lambert & Beris, 2009, p. 109). “Symptoms such as weakness, fatigue, drowsiness, angina, syncope, and dyspnea on exertion can indicate anemia. Vertigo, headache, pulsatile tinnitus, amenorrhea, loss of libido, and gastrointestinal (GI) complaints may also occur. Heart failure or shock can develop in patients with severe tissue hypoxia or hypovolemia” (Braunstein, 2019).

Exploration of Ms. RN’s risk factors, symptoms and physical findings strongly favor a diagnosis of anemia. First, Ms. RN has a history of abnormal blood loss through epistaxis and menorrhagia that serve as risk factors for anemia. Second, she has associated symptoms of fatigue and dyspnea. Last, physical findings include tachycardia, a smooth tongue, pale conjunctiva, and positive fecal occult blood.

There are more than 400 causes of anemia, but they can be categorized simply. Anemia occurs when the body makes too few red blood cells (RBCs), destroys too many RBCs or loses too many RBCs (US Department of Health and Human Services, 2011). Ms. RN will require additional diagnostic testing to determine if she does, indeed, have anemia and which type of anemia she has. 

Several common causes of anemia are unlikely for Ms. RN because she lacks their corresponding risk factors and symptoms: vegan diet and neuropathic “stocking-glove” paresthesias for vitamin B12 deficiency anemia; alcoholism for folate deficiency anemia; genetic predisposition for hemoglobinopathies; petechiae for thrombocytopenia or platelet dysfunction; drug and infection history or jaundice and dark urine associated with hemolytic anemias; cancer, rheumatic disorders, chronic inflammatory disorders and splenomegaly associated with bone marrow suppression anemias; melena, epistaxis, hematochezia, hematemesis, or menorrhagia indicating abnormal blood loss as a source of anemia; and diffuse severe bone or chest pain for sickle cell disease (Braunstein, 2019).

Diagnostic tests for anemia include complete blood count (CBC), including white blood cell (WBC) and platelet counts, red blood cell volume, red blood cell hemoglobin and hemoglobin concentration, red blood cell distribution width, and examination of a peripheral blood smear to examine cell number and shape. In addition, a reticulocyte count measures how well bone marrow is compensating for anemia. Anemia is an indication of a problem rather than a disease process, and these tests indicate the etiology (Braunstein, 2019).

Because Ms. RN has a “fingerprint” symptom for iron deficiency anemia, initial testing will also include the measurements of blood iron and ferritin–the iron reserve. Normal values for adults are 10 to 30 micromoles per liter (mmol/L) of iron and 20 to 200 micrograms per liter (mg/L) of ferritin for women. Iron deficiency anemia is indicated with iron is less than 10 mmol/L and ferritin is less than 10 mg/L (National Heart, Lung, and Blood Institute, 2019).

Ms. RN’s lab results are conclusive for anemia with red blood cell count of 3.3 trillion cells/L (normal 4.2 to 6.2 million/mm3), hemoglobin level of 7.7 g/dL (normal 12 to 18 g/dL), and hematocrit of 28.6% (normal 37% to 54%) (McCance & Huether, 2019). Iron deficiency anemia is confirmed with blood iron level of 8 mmol/L and ferritin of 9 mg/L.

Ms. RN begins iron replacement therapy with an initial dose of 150 mg/day. She will follow up with her primary care physician to identify and resolve sources of abnormal menstrual and GI bleeding. Hematocrit levels should improve within one to two months of therapy. The course of treatment usually continues for 6 to 24 months after bleeding is resolved, but, due to menorrhagia, Ms. RN may need replacement therapy until menopause (McCance & Huether, 2019, p. 936). Improved iron levels, iron reserves and hematocrit levels upon treatment with iron replacement therapy will, ultimately, confirm her diagnosis with iron deficiency anemia.

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