15 Diseases Difficult To Diagnose

With some diseases, healthcare providers use a process called differential diagnosis to narrow down and confirm a diagnosis.

When you have strange pains, mysterious digestive issues, or other unexplained symptoms, you may hope visiting a healthcare provider will solve your health woes. However, occasionally, healthcare providers have just as much trouble identifying certain disorders and conditions.

Some health conditions present very similarly. For example, muscle pains and aches are symptoms of fibromyalgia, rheumatoid arthritis (RA), and osteoarthritis (OA). So, healthcare providers often use a process known as differential diagnosis. 

With a differential diagnosis, a healthcare provider gathers information on your symptoms and health history. Then, they may perform a physical exam. Based on that information, the healthcare provider will list possible conditions, then order tests to come to a final diagnosis.

However, that process is often lengthy and costly. What's more, even then, some illnesses are still hard to diagnose because no definitive tests exist. 

Recognizing diseases that are difficult to diagnose is key since about 5% of people in the United States receive a wrong diagnosis yearly. Still, with a focus on differential diagnosis and education on several diseases, healthcare providers can lessen diagnostic delays and errors.

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Often, an inflamed or burst appendix is easy to identify. Typical appendicitis symptoms include abdominal pain, tenderness around the belly button, nausea, and a low-grade fever.

However, appendicitis can be hard to diagnose. For example, some children may not present typical symptoms. Also, appendicitis may present different symptoms, depending on the position of the appendix.

Also, in some cases, painful symptoms subside if the appendix ruptures. However, symptoms likely return within a few days after the rupture. A ruptured appendix may cause a life-threatening infection called peritonitis if intestinal fluids flow into the abdominal region.

Celiac Disease

Celiac disease causes an immune reaction to gluten that triggers inflammation in the small intestine. On average, people with celiac disease wait 3.5 years for a proper diagnosis.

In theory, people with celiac disease would have digestive problems when eating gluten, found in wheat, barley, and rye. Still, some people with celiac disease are asymptomatic. In other words, they do not have any symptoms.

In people with symptoms, celiac disease may cause the following:

  • Itchy skin
  • Headaches
  • Joint pain
  • Acid reflux
  • Bloating

However. Those symptoms may resemble other conditions, like irritable bowel syndrome (IBS). So, a healthcare provider may order tests to confirm celiac disease. For example, a blood test can diagnose celiac disease regardless of symptoms. Also, endoscopy can specify any damage to the small intestine.

Cluster Headaches

Cluster headaches are extremely painful but rare, affecting about 0.1% of people in the United States. Cluster headaches occur close together, often on the same day, and last 15 minutes to three hours on average. 

In some cases, cluster headaches cause nasal congestion, similar to sinus headaches. So, a healthcare provider might mistakenly treat cluster headaches as a sinus infection. While decongestants alleviate sinus headaches, they do not help with cluster headaches.

However, unlike sinus headaches, cluster headaches occur several times daily at the same time. Also, people with cluster headaches may have a week- or month-long flare with periods of remission. Often, seasonal changes trigger cluster headaches.


Some people with type 2 diabetes have the condition for years before diagnosis. About 88 million adults in the United States have prediabetes, which is high blood sugar. However, some people may not regularly see a healthcare provider to check their blood sugar levels.

If left untreated, type 2 diabetes can cause life-threatening damage to the body, like vision problems or numbness in the feet or hands. To avoid those problems, watch for early symptoms like increased thirst or hunger, frequent urination, sudden weight loss, and fatigue.


Many people learn to expect pain during their periods. Therefore, some people might overlook the possibility of endometriosis

Endometriosis is when tissue similar to the one that lines the inside of the uterus grows outside of it. People with endometriosis often report pelvic pain that flares during periods and heavy menstrual bleeding, which can worsen over time.

Imaging tests, like an ultrasound or MRI, can sometimes detect endometrial lesions that cause pelvic pain. However, the only way to properly diagnose endometriosis is laparoscopy, a minimally-invasive surgery. Like all types of surgery, laparoscopy comes with risks and may be costly.

So, due to the dismissal of painful symptoms and costly, invasive diagnostic tests, people often have endometriosis for seven to nine years before receiving a proper diagnosis. Awareness and less invasive tests can help reduce that delay. 


Fibromyalgia, which causes widespread muscle pain, often involves "medically unexplained symptoms." In other words, people with fibromyalgia describe ailments that don't appear to have an apparent physical cause.

Fibromyalgia may cause several symptoms, such as:

  • Widespread muscle pain
  • Fatigue
  • Mental fog
  • Anxiety and depression
  • Gastrointestinal (GI) upset

Those symptoms are nonspecific and often signal conditions like IBS, GERD, or hypothyroidism. What's more, lab tests usually do not find abnormalities in people with fibromyalgia.

However, the differential diagnosis process can help rule out other diseases to confirm fibromyalgia. For example, health history and physical exams are key.


Hypothyroidism, also known as underactive thyroid, is when the thyroid gland does not produce enough hormones that help regulate weight, energy, and mood.

In the early stages, hypothyroidism symptoms are subtle and can include the following:

  • Fatigue
  • Depression
  • Weight gain
  • Dry skin
  • Muscle aches
  • Goiter, which is an enlarged thyroid that makes the neck look swollen

Often, hypothyroidism symptoms can look like depression or fibromyalgia. Also, hypothyroidism is most common in women over 60. So, people might attribute symptoms to aging. 

However, what sets hypothyroidism apart from those illnesses is an enlarged thyroid that makes the neck look swollen, also known as a goiter. People with hypothyroidism may feel like their throats are full and flares of neck pains or sore throats.

Also, healthcare providers can confirm hypothyroidism with thyroid tests, like TSH, T3, T4, and thyroid antibody blood tests. With an underactive thyroid, levels of those hormones may be lower than average.

Inflammatory Bowel Disease

Two types of inflammatory bowel disease (IBD) are Crohn's disease and ulcerative colitis. Both conditions cause digestive tract inflammation, abdominal pain, and diarrhea.

There is no single test for IBD. Instead, healthcare providers diagnose IBD using a mix of clinical findings, a physical exam, lab tests, imaging, and procedures. Essentially, healthcare providers diagnose the condition by ruling out others. 

For example, IBD symptoms often mimic parasitic infections like giardia and amebiasis. A healthcare provider may study a stool sample to rule out those infections.

Also, a healthcare provider may order lab tests for inflammatory markers, such as elevated high-sensitivity C-reactive protein levels. Likewise, imaging, such as an abdominal X-ray, ultrasound, CT scan, and MRI, can find bowel obstructions. 

Procedures like endoscopy and colonoscopy also allow a healthcare provider to obtain a sample for biopsy and confirm IBD.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a chronic condition that affects the large intestine. IBS symptoms include:

  • Abdominal pain
  • Cramping
  • Bloating
  • Diarrhea
  • Constipation

Those symptoms are similar to celiac disease, colon cancer, and IBD. Therefore, a healthcare provider may order several tests to rule out those conditions. For example, a blood test can rule out celiac disease. Also, stool samples can rule out infections, including parasitic infections.


A butterfly-shaped rash across the cheeks is one of the most distinctive signs of lupus, a chronic inflammatory disease. However, a rash is not always present.

What's more, other lupus symptoms are nonspecific and may look like other diseases. In addition to a rash, lupus symptoms include:

  • Painful, swollen joints
  • Muscle aches and pains
  • Fever
  • Chest pain
  • Hair loss
  • Discolored fingers and toes
  • Increased sensitivity to the sun
  • Ulcers in the mouth
  • Swollen lymph nodes
  • Fatigue

Since there is no one way to diagnose lupus, diagnosis may take several years to confirm. Still, clinical findings, a physical exam, blood tests, and skin and kidney biopsies usually help with diagnosis.

Lyme Disease

Lyme disease is a tick-borne illness that causes flu-like symptoms and a recognizable bulls-eye rash. However, about 30% of people with Lyme disease never develop a rash. Likewise, others with a rash may have other symptoms like burning and itching, while others do.

So, Lyme disease can be hard to diagnose. What's more, people with Lyme disease develop antibodies. However, most tests that check for those antibodies cannot detect them immediately. So, if people test too soon, their test may not detect Lyme disease.

Still, healthcare providers can diagnose Lyme disease by taking a detailed health history and conducting a physical exam. Also, ruling out other diseases—skin conditions like cellulitis and contact dermatitis—can help.


For many people with chronic migraines, nothing could be more evident than severe headaches. Migraine symptoms also include:

  • Intense throbbing or pulsing
  • Nausea
  • Feeling weak
  • Sensitivity to light and sound

However, migraine symptoms vary between people. Some people may get migraines without knowing it. In contrast, others may get migraines so severe that they develop paralysis.

For people who get mild migraine symptoms, healthcare providers may diagnose medications that do not properly treat chronic migraines. However, a neurologist can typically rule out other possibilities to make a correct diagnosis.

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease in which the immune system mistakenly targets and attacks nerve cells. That abnormal immune system response disrupts communication between the brain and the rest of the body. 

Often, some of the early symptoms of MS are numbness, weakness, or tingling in one or more limbs. However, each case is different. There are different types of MS, some of which cause flares and remission periods. 

If a healthcare provider suspects MS, clinical findings, a neurological exam, and MRI can help confirm the diagnosis.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) happens if the ovaries make too many androgens, which are male sex hormones. Excess androgen levels typically cause irregular periods, unexplained weight gain, and difficulty getting pregnant.

Many people with PCOS have enlarged ovaries with several small cysts. Still, not everyone with PCOS has enlarged ovaries, and not everyone with enlarged ovaries has PCOS.

A blood test can detect excess androgens in the blood. Also, people with PCOS may have infrequent or prolonged periods and abnormal hair growth on the face and body.

Rheumatoid Arthritis

Rheumatoid arthritis (RA), an autoimmune disease, typically causes muscle aches and joint pain. Unlike osteoarthritis, a "wear and tear" type of arthritis that appears as people age, RA can occur at any age.

The early stages of RA can look like many other health conditions. Some people may only have aches or stiffness in the joints, which could be caused by many different things.

However, blood tests can help detect the presence of inflammation in the body. Also, to accurately diagnose RA, a healthcare provider must detail a person's health history and conduct a physical exam.

A Quick Review

Many health conditions have nonspecific symptoms that resemble several other illnesses. Diseases that are difficult to diagnose may have lengthy diagnostic delays or be inaccurately diagnosed.

Still, healthcare providers can use the process of differential diagnosis, including several tests, to narrow down and confirm a diagnosis. Also, spreading awareness of those health conditions can help.

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