The clinical diagnosis of disease is based on the recognition and proper interpretation of its manifestation, commonly known as signs and symptoms. The term symptom is used for features that are recognized subjectively by the affected person, whereas signs are more objectively noticeable and can be recognized by the nurse or doctor during physical examination, by ancillary methods and tests, by another person associated with the patient, or by the patient himself or herself.

Most symptoms and many signs are usually described during the medical history interview when the patient pre-sents to the physician. Other signs are discovered during the physical examination and clinical work-up. The most important findings detected by physical examination are listed in Table 2-1.

Table 2-1 Clinical Findings That Can Be Noted During Physical Examination

The ultimate significance of all signs and symptoms discovered during the initial work-up is not always obvious, and the physician must often use inductive and deductive reasoning in interpreting them. Often it is necessary to formulate one or more working hypotheses and develop a list of various similar conditions to be included in the differential diagnosis. Many of these conditions must be excluded by additional testing until the tentative diagnosis is reached (Fig. 2-1). This tentative diagnosis functions as a working hypothesis until confirmed by other means, which often include definitive or pathognomonic pathologic findings. Prior to instituting any therapy, it is desirable to make the definitive diagnosis formulated in terms of precise etiology, pathogenesis, pathophysiology, and underlying pathology.

The signs and symptoms of various diseases may be classified as systemic or centered on a specific organ system. The important and common systemic signs and symptoms are described here, but most of the organ system-centered signs and symptoms will be discussed in subsequent chapters. Table 2-2 contains a list of the most common systemic and organ-centered signs and symptoms encountered in general medical practice.

Table 2-2 Most Common Signs and Symptoms Encountered in General Medical Practice

Fatigue Pain Anxiety
Fever Headache Depression
Weakness Back pain and joint pain Insomnia
Anorexia Chest and abdominal pain Irritability
Weight loss Cough Loss of mental prowess
Weight gain Nasal discharge Loss of consciousness
Swelling* GI symptoms Dizziness and vertigo
Itching and rash* Shortness of breath Gait and movement disorders
Bleeding* Palpable “lumps and bumps” Hearing loss
    Visual problems

* May be both systemic and localized. Note also that this classification includes certain entities that could belong to more than one rubric and that some physical signs and symptoms are actually manifestations of psychological/neurologic disturbances.


Fatigue, or tiredness, is the normal physiologic response to demanding exercise or any other prolonged physical or mental activity. Physiologically, it can be most easily measured in the muscles, which, when fatigued, cannot maintain a contraction or respond progressively slowly to stimuli, until finally no reaction can be elicited from them. In such cases the muscles are simply depleted of fuel in form of nutrients (e.g., glycogen) and energy-rich compounds like creatine phosphate or adenosine triphosphate (ATP) (Fig. 2-2). The accumulation of lactic acid and the acidification of the internal milieu inhibit actin–myosin interaction and muscle cell contraction. Increased concentration of phosphorus in the cytosol affects the release of calcium from internal stores (e.g., sarcoplasmic reticulum), preventing its catalytic action on the contractile fibers.


Anorexia Lack of appetite sometimes associated with aversion to food.

Cachexia Generalized weakness, wasting, and weight loss caused by cancer or other debilitating chronic diseases.

Coma State of deep unconsciousness accompanied by a loss of responsiveness to external stimuli. The depth of coma can be graded; in the most severe form it is irreversible.

Edema Localized or generalized excessive accumulation of fluid in the interstitial spaces of various tissues or body cavities. When generalized it is called anasarca.

Fatigue Feeling of tiredness and inability to perform optimally. It occurs physiologically at the end of prolonged effort or as a sign of disease.

Fever (pyrexia) Increased body temperature over the upper limits of normal. It may be a physiologic response to endogenous or exogenous influences that accelerate the metabolism or raise the body temperature. Most often it is a consequence of diseases that produce endogenous pyrogens acting on the hypothalamic thermoregulatory center.

Headache (cephalalgia) Pain in the head caused by a variety of mechanisms affecting the intracranial or extracranial structures of the head.

Hemorrhage (bleeding) Escape of blood from the vessels into the tissues, hollow organs, or external environment.

Pain Unpleasant or distressing feeling based on a psychological reaction to sensory stimuli generated in specialized nerve endings in the skin, muscles, and many internal organs.

Sign Manifestation of a disease that can be recognized objectively by medical examination.

Symptom Manifestation of a disease recognized subjectively by the affected patient.

Syncope (faint, swoon) Temporary loss of consciousness related to a sudden onset of generalized cerebral ischemia.

Weight loss Voluntary or involuntary loss of body mass, empirically defined as exceeding 5% of the body weight over a 6-month period.

Psychological fatigue can ensue after prolonged mental effort, excitement, stress, and even lack of sleep. The underlying pathogenesis of psychological fatigue is less well known. Both muscle fatigue and psychological fatigue are relieved by rest.

Fatigue is a common sign of disease.

Fatigue is a common complaint, especially in chronic diseases and after surgery or trauma. Sometimes it is even the leading symptom prompting the patient to see the doctor. Patients use the term fatigue rather loosely, and thus it is important to determine whether they mean exhaustion, lack of energy, weakness, or even boredom. In 50% to 60% of cases the feeling of fatigue is psychogenic, in 30% to 50% of cases it has an organic cause, and in the remaining 20% it is of undetermined cause. If the patient is older than 40 years of age, organic disease is found to be the underlying cause of fatigue in over 80% of cases.

Psychogenic fatigue (also known as central fatigue) is characterized by an aversion to doing anything. It is usually present before the patient gets out of bed. It fluctuates during the week and is usually less pronounced over the weekend or on holidays. It is not relieved by rest. Anxiety states, depression, and sleep disorders also may cause fatigue, which is most likely multifactorial.

Pharmacologic causes of fatigue include sleeping pills, tranquilizers, and some antihypertensive drugs. Cytostatics used in the treatment of cancer have complex effects on the intermediary metabolism and can also cause fatigue by inhibiting the normal energy-generating processes or by causing the formation of toxic by-products. Recreational drug abuse is frequently associated with fatigue.

Fatigue related to systemic disease is usually mild or nonexistent in the morning but worsens during the day. It may be caused by hypothyroidism, adrenal insufficiency, chronic heart disease, lung diseases, hematologic diseases such as anemia, myelodysplastic syndrome or multiple myeloma, cirrhosis, uremia, cancer, chronic infections, and autoimmune disorders, to mention the most important ones. Neuromuscular disorders, such as muscular dystrophy, myasthenia gravis, multiple sclerosis, and Parkinson’s disease cause fatigue with muscle weakness. The most common organic causes of fatigue are listed in Table 2-3.

Table 2-3 Organic Causes of Fatigue

Cardiovascular Congestive heart failure, MI
Respiratory Chronic obstructive pulmonary disease, asthma
Hematologic Anemia, MDS, multiple myeloma
Endocrine Hypothyroidism, hyperthyroidism, adrenal insufficiency
Hepatic Cirrhosis, chronic hepatitis
Renal Chronic renal failure
Neurologic/muscular Myopathies, neuropathies, myasthenia gravis, multiple sclerosis
Cancer Any form of cancer can cause fatigue
Autoimmune Rheumatoid arthritis, SLE
Other Obesity, malnutrition, alcohol abuse, effects of medication, radiation therapy

MDS, myelodysplastic syndrome; MI, myocardial infarction; SLE, systemic lupus erythematosus.

Chronic fatigue syndrome is a clinical entity characterized by long-standing tiredness with no obvious physical or psychological basis. The cause of this syndrome is unknown, but it seems to be linked to psychological reactions to minor stresses in daily life. Many other explanations have been proposed and explored, but no definitive conclusion has yet been reached. The hypothesis that it is related to viral infection is not proven, even though many patients complain of upper respiratory and pharyngeal swelling and some even have enlarged lymph nodes.

The clinical diagnosis of chronic fatigue syndrome is made only if the symptoms last more than 6 months. Muscle and joint pain are common, and headache is a prominent complaint. The extent of fatigue worsens during the day and after exertion. Other symptoms include fever that comes and wanes, abdominal pain, muscle pain, and difficulty in concentrating or sleeping. Organic symptoms such as sore throat and enlargement of lymph nodes may suggest chronic infection or neoplasia, but detailed clinical studies usually cannot prove any structural abnormalities. The laboratory studies are usually noncontributory. The treatment should include supportive measures and should be planned for each person individually, but no treatment regimen devised to date has proved successful.

Weight Loss

Weight loss results when the intake of calories is insufficient to meet the energy requirements of the body. Weight loss may be voluntary, as occurs in persons who are dieting, or involuntary, as when a caloric deficit occurs due to exogenous or endogenous factors beyond voluntary control. Medically significant involuntary weight loss is empirically defined as loss of 5% of body weight documented over a 6-month period.

Weight loss due to a loss of fluid is called dehydration.

Overall, weight loss can result under the following conditions:

The initial work-up for a patient who complains of weight loss must first determine if the weight loss is voluntary or involuntary. In cases of involuntary weight loss, document not only the extent but also the duration of the loss and investigate the possible causes. Determine whether the food intake is normal or decreased (Fig. 2-3). If food intake is adequate the weight loss might be related to inadequate absorption or to excessive loss or utilization of calories caused by various metabolic diseases. On the other hand, if food intake is decreased, determine whether the patient has normal or decreased appetite and then ascertain the causes of these conditions.

Cachexia is characterized by involuntary weight loss caused by the complex effects of cancer or chronic diseases on the body.

Cachexia is a syndrome characterized by weakness and weight loss encountered in patients who have cancer or certain chronic infectious diseases, such as tuberculosis or AIDS. The weight loss is typically accompanied by muscle wasting, and thus the patient feels tired, weak, and unable to work. The overall basal metabolic rate is increased, with changes involving the metabolism of proteins, carbohydrates, and fats. Increased degradation of proteins is accompanied by increased BUN and creatinine, anemia, and hypoalbuminemia. Reduced utilization of glucose and increased gluconeogenesis result in hyperglycemia, increased concentration of plasma lactate, and insulin resistance. Free fatty acids in the blood are increased due to unsuppressed free fatty acid mobilization from peripheral fat stores.

The pathogenesis of cachexia in cancer patients is complex and not fully understood. Several factors play a potential role, such as:

image Obstruction of the gastrointestinal tract. Carcinoma of the stomach and esophagus may interfere with the ingestion of food. Carcinoma of the head of the pancreas may obstruct the common bile duct and prevent the influx of bile or pancreatic juices.

image Anorexia. Patients lose appetite, which in part could be due to a loss of taste for sweet, sour, and salty foods. Some patients, like those who have gastric or liver cancer, develop aversion to meat, whereas others develop a dislike for coffee or chocolate.

image Early satiety. Increased blood glucose due to poor utilization or low levels of insulin may suppress appetite. Increased plasma concentration of proteins and amino acids mobilized from the muscle may act on the satiety center and suppress appetite.

image Increased energy expenditure. The tumor acts as a parasite and may consume more energy than normal tissues. In addition, the competition for nutrients between the tumor and the host leads to metabolic disturbances in the host, including hypermetabolism, which, in turn, leads to an increased energetic inefficiency.

image Cytokines released in response to tumor growth. Tumor necrosis factor (also known as cachectin), interleukin 6 (IL-6), and many other cytokines could be responsible for anorexia, hypermetabolism, and many other metabolic abnormalities, such as muscle proteolysis and apoptosis.

image Therapy. Weight loss is in many cases due to chemotherapy, known to cause nausea, vomiting, diarrhea, altered taste, and pain. Surgery could also cause increased weight loss by increasing energy expenditure or by affecting food intake.


Fever is an abnormal elevation of the body temperature above the upper limit of normal daily variation (i.e., >37.8°C [100°F] orally or 38.2°C [100.8°F] rectally). Remember that body temperature is lower in the morning (37.2°C) and reaches it upper limit of normal (37.7°C) in the evening. Overall, the temperature is lower in older people, hence the clinical dictum “the older the colder.”

Fever results from action of endogenous pyrogens on the hypothalamic thermostat.

Under normal conditions the hypothalamic thermoregulatory center adjusts the peripheral loss of heat to match heat production, thus keeping the body temperature in a range roughly between 37°C and 38°C. In many inflammatory diseases the set point of the hypothalamic thermostat occurs at a higher temperature, which reduces the dissipation of heat in the periphery and leads to hyperthermia. This resetting of the thermostat results from the action of cytokines released from activated macrophages and, to a lesser extent, activated T lymphocytes. Because they cause fever, these mediators of inflammation are called B lymphocytes. The most important among them are interleukins (IL-1α, IL-1β, IL-6), tumor necrosis factors (TNF-α,TNF-β), and interferons (IFN-α, IFN-β, IFN-γ).

Endogenous pyrogens do not act directly on the thermoregulatory center. Instead, they act on the endothelial cells of a highly vascular part of the wall of the third ventricle, called organum vasculosum laminae terminalis (OVLT). Under the influence of pyrogens the endothelial cells of OVLT produce prostaglandin PGE2, which diffuses into the adjacent hypothalamus and, by acting on the thermoregulatory center, raises the set point for thermoregulation. The signals from the thermoregulatory center lead to vasoconstriction of dermal vessels, cessation of sweating, and shivering of muscles, thereby reducing the dissipation of heat (Fig. 2-5).

Fever can result from infections or noninfectious disease.

Fever is a common sign of infections, but it can occur in the course of many other diseases (Table 2-4). Thus it is customary to classify fever as infectious or noninfectious. If the cause cannot be identified, it is classified as fever of unknown origin (FUO).

Table 2-4 Common Causes of Fever

Fever of infectious origin. Almost any acute or chronic infectious disease may cause fever. As a rule, infection should be the first diagnosis considered in all febrile patients, especially if the fever is of sudden onset, associated with other signs of inflammation, and localizing symptoms point to a site of infection. Only after infection has been excluded as a possible cause is it advisable to consider other causes of fever.

Fever related to noninfectious diseases. Endogenous pyrogens can be released by inflammatory cells infiltrating various organs affected by autoimmune diseases, following tissue necrosis after infarction, in crystalline arthropathy (e.g., gout), and as part of a drug reaction. Pyrogens may be released from many other cells, especially endothelial cells in the blood vessels, fixed macrophages such as hepatic Kupffer cells, glial cells, and dermal Langerhans cells. Parenchymal tissue cells—such as keratinocytes of the skin, nasal and bronchial, or intestinal epithelial cells—also can produce cytokines that act as pyrogens. Tumor cells are a well-known source of pyrogens. Fever is especially common in patients who have lymphoma, renal cell carcinoma, and primary or secondary tumors of the liver.

Fever of unknown origin. For clinical purposes FUO is defined as temperature over 38.3°C (101°F) lasting at least 3 weeks, for which the cause could not be found after 1 week of intensive investigation. Most diseases that evade early diagnosis turn out to be either infectious or neoplastic. Even under the best of all possible conditions, the cause of fever cannot be determined in about 10% to 15% of patients.

Acute fever may have adverse effect on several organs.

It is generally believed that mild elevation of body temperature helps the body combat infection by accelerating the metabolism and all defense mechanisms. Roughly speaking, for each degree (centigrade) rise in temperature, the basal metabolic rate increases by approximately 10%, and otherwise healthy individuals can readily tolerate body temperature up to 40.5°C (105°F). As temperature rises, the heart and respiratory rates are increased. The body’s own attempts to reduce the temperature include sweating and chills. Fever also affects the central nervous system, typically causing headache. High temperatures may cause convulsions, especially in children.

Extreme hyperthermia beyond 42.1°C (108°F) may damage the endothelium of blood vessels and cause disseminated intravascular coagulation (DIC). Microvascular thrombosis leads to ischemic tissue injury, especially in the brain and the heart. Hypotensive shock and neurologic signs of cerebral ischemia develop, and the patient may fall into coma and die.

Heat stroke results from prolonged exposure to high environmental temperatures. The affected person has high fever, but does not sweat, indicating a failure of central thermoregulation. Most often it is seen during summer heat waves, typically affecting the elderly and those who have been incapacitated by alcohol or drugs. These patients usually lapse into coma and often die.


Pain is an unpleasant feeling; that is, a psychological reaction to sensations that begin with the stimulation of peripheral sensors. Pathogenetically it includes four sequential components:

The pain pathway has two parts: the peripheral part, involving the nociceptors and sensory nerves, and a central part, involving the cortical centers (Fig. 2-6).

Nociceptors. As the term implies (nociceptor is derived from the Latin words nocere, meaning hurting, receptor, meaning receiver), the main function of receptors for pain is to recognize mechanical, thermal, or chemical impulses that could damage the body and consequently elicit a reaction that will minimize that damage. Nociceptors are free nerve endings widely distributed in the skin, soft tissues, skeletal muscles, and joints. Internal organs are sparsely supplied, but almost all major organs, except the brain, have nociceptors.

Nociceptors can be classified as thermal, mechanical, chemical, or polymodal nociceptors. They include fast myelinated mechanical Aδ fibers and slow unmyelinated polymodal C fibers. In addition to nociceptors pain can originate from other sensory stimuli. For example, the distention of the intestines stimulates local mechanoreceptors, causing visceral dull pain. Pacinian corpuscles, the rapidly adapting mechanoreceptors of the skin, are also found in the mesentery and the pancreas, and their stimulation generates pain.

The nociceptors respond to external stimuli by transmitting afferent nerve signals and also by secreting mediators of inflammation such as substance P. The nerve impulses also travel efferently through interconnecting axons (axonal reflex), provoking a vascular response. The release of these mediators acts on endothelial cells of the local blood vessels, inducing increased permeability and also stimulating them to secrete cytokines. Hence the entire area becomes inflamed (neurogenic inflammation). The mediators of inflammation, such as bradykinin or cytokines, act on nociceptors, increasing their responsiveness (peripheral sensitization). Peripheral sensitization is associated with hyperalgesia, an increased feeling of pain and a reduced threshold to pain. Conversely, stimulating other sensory endings, such as low-threshold mechanoreceptors Aα and Aβ, may reduce the sensation of pain.

Central nervous system response. From the early stages of pain transmission, as soon as the impulses reach the sensory centers in the brain, pain has also a psychological component. It evokes emotions and can be modulated by cognitive mechanisms. For example it is well known that in the heat of the battle or during sporting events an injured person can withstand pain that would otherwise be perceived as intolerable. The intensity of the pain can be reduced by reducing the level of consciousness (e.g., by anesthesia), distracting the person’s attention, and by a variety of palliative effects that produce a placebo effect. Fear and expectations also may modify the perception of pain.

The reaction to pain can be modified in the brain by cortical impulses and by the activation of other subcortical centers. At the cellular level a major role is played by small-molecular-weight polypeptides called endorphins. These polypeptides bind to opioid receptors on sensory neurons, modifying the perception of the pain. Opioid drugs and other analgesics also have similar effects.

Pain can be classified as organic or psychogenic.

Because pain has both sensory and psychological components, it is best to classify it as predominantly organic or predominantly psychogenic (Fig. 2-7). Organic pain can be explained in terms of underlying pathology, whereas psychogenic pain eludes such explanation and its cause may be quite puzzling.

Organic pain resulting from excessive or prolonged stimulation of peripheral nerve endings is called nociceptive pain (Fig. 2-8). Nociceptive pain, which originates in the skin and subcutaneous tissues, typically corresponds to innervation of anatomic dermatomes and is called somatic pain. Somatic pain is typically sharp, severe, and pricking. Pain originating from the parietal peritoneum or pleura is known as parietal pain but in essence is identical to somatic pain. Parietal pain can be localized or diffuse. Localized pain, such as pain in the right lower abdominal quadrant in appendicitis, can pinpoint the nature of the disease that precipitates it. However, pain can also be referred to a site quite distant from the site of original pathology. Diffuse parietal pain is typically seen in peritonitis when the entire surface of the abdominal cavity is inflamed. Typically the patient tries not to move, and any movement, such as coughing or vomiting, exacerbates the pain. Pain originating from the nerve endings in internal organs is called visceral pain. Visceral pain is usually poorly localized and is most intensively felt in the midline of the abdomen or thorax. Pain is often dull, but it may also be colicky and cause a feeling described by the patients as gnawing or burning.

Neuropathic pain results from an injury to the peripheral sensory nerves or nerves in the spinal cord and brain. Typical examples of neuropathic pain are back pain due to the compression of spinal nerves by a degenerated intervertebral disk, herpes simplex neuropathy involving the facial nerve, or pain due to spinal cord injury.

Psychogenic pain cannot be readily explained, but that does not preclude its resulting from some underlying pathology. Typical examples are chronic headache and back pain, which can be quite crippling and represent some of the most common problems encountered in daily medical practice.

Oct 29, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on SIGNS AND SYMPTOMS
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