Scleroderma: Pathology review

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Scleroderma: Pathology review

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Preview

A 38-year-old woman comes to the emergency department for evaluation of altered mental status that began five hours ago. She is accompanied by her husband. Past medical history is notable for asthma and diffuse scleroderma. On arrival, her temperature is 37.6°C (99.7°F) and blood pressure is 183/121 mmHg. On physical examination, the patient is oriented to self but neither time nor place. Diffuse thickening of the skin is observed, and contractures are present in the bilateral fingers. Laboratory testing is obtained, and results are as follows:  
 

 Laboratory value  Result 
 Hemoglobin  10.7 g/dL 
 Leukocyte Count  7,300/mm3 
 Platelet Count  80,000/mm3 
 Blood Urea Nitrogen  35 mg/dL 
 Creatinine, Serum  2.0 mg/dL 
Which of the following is the next best step in the management of this patient’s condition?

Transcript

Content Reviewers:

While doing your rounds, you see Rosa, a 35-year-old woman who has complained of puffy hands and feet for the past 4 months.

On examination, the skin on the limbs and trunk is stiff and shiny, with decreased markings.

Other important findings are sclerodactyly, Raynaud's phenomenon, and digital ulceration.

Pulmonary function tests were performed as well, and they showed a pattern suggestive of restrictive lung disease.

Then you see Haruki, a 65-year old who says that he noticed skin changes recently, stating that the wrinkles on his face have disappeared.

He also said that his acid reflux got worse in the past 6 months.

On examination, his hands show Raynaud's phenomenon and sclerodactyly.

The skin on his face and the arms below the elbow were tight, shiny, smooth, with no wrinkles.

Pulmonary function tests are normal.

Blood tests were performed in both cases, showing increased serum levels of anti-Scl 70 and and-RNA polymerase III antibodies in Rosa, and increased anti-centromere antibodies in Haruki.

Now, both seem to have scleroderma.

Scleroderma refers to systemic sclerosis, a rare autoimmune disorder in which normal tissue is replaced by thick, dense collagen.

It affects the skin, blood vessels and internal organs.

Now, there are two main types of scleroderma, diffuse cutaneous systemic scleroderma; and limited cutaneous systemic scleroderma, which was formerly called CREST syndrome.

The condition’s pathology is not completely understood, but it’s believed that some individuals have a genetic predisposition to scleroderma which is triggered by external factors.

These triggers include: viral infection by cyto-megalo-virus and parvovirus B19; exposure to silica dust, organic solvents, vinyl chloride; and medication like cocaine, bleomycin, and pentazocine.

Okay, for pathology, scleroderma usually starts with an injury to the endothelial cells that line the interior surface of small blood vessels, causing non-inflammatory vasculitis.

These cells then start expressing adhesion molecules that T cells stick to.

T cells then migrate outside of the blood vessels and into the surrounding tissue, where they start releasing cytokines, which attract other immune cells that further damage small blood vessels; and activate fibroblasts that produce and deposit collagen.

In time, collagen builds up and forms a highly stable matrix that is responsible for the stiffness of the tissue.

This buildup of excess connective tissue is called fibrosis.

Finally, blood vessel damage and fibrosis reduce blood flow to the tissue and cause ischemic tissue damage.

There is another type of immune cell that plays a role in scleroderma, B cells.

What’s causing them to activate is currently unknown, but we do know that activated B cells produce antinuclear antibodies, or ANA, that bind to the content of the nucleus that leaks out of damaged or dead cells.

Some ANA’s are both highly specific to Scleroderma so they are very high yield!

These include anti-Scl 70 , which targets DNA topoisomerase I, anti-RNA polymerase III, and anti-centromere antibodies.

For symptoms of scleroderma, both types affect women three times more often than men, especially women over 50 years of age.

The two types can affect the same organs and cause similar symptoms, but the disease progression can differ.

Let’s start with diffuse cutaneous systemic scleroderma, where symptoms are usually rapidly progressive and its associated with visceral involvement early in its evolution.

Ok, so skin lesions start in the fingers and move up across the arm to the shoulders, neck, and face.

At first, the affected skin is swollen and puffy.

Later when fibrosis develops, the skin becomes tight, stiff, shiny, smooth, but with no wrinkles, especially around the fingers and dorsum of the hands.

When it happens on the fingers it is called sclerodactyly, which can cause fingers to curl inward, so the hand becomes shaped like a claw.

On the face, the mouth can become narrow, which is called microstomia, and the nose becomes beaked.

Sometimes, calcium can deposit in the skin and subcutaneous tissue through an unknown mechanism, and this is called calcinosis cutis.

Small vessel involvement can lead to Raynaud's phenomenon, where the distal parts of the fingers turn white when exposed to cold, due to vasospasm.

Then the color changes to blue and finally red as the blood vessels expand to get enough oxygen-rich blood to the fingers.

In time, because vasospasm can cause ischemia, individuals might develop digital ulcerations.

Scleroderma can cause telangiectasias as well, also known as spider veins, which are small dilated blood vessels that can occur near the surface of the skin or mucous membranes.

Another common site of damage is the joints, where symptoms are typically non specific and can include joint pain, stiffness, and restricted joint mobility.

In the gastrointestinal tract, there can be esophageal dysmotility and incompetence of the lower esophageal sphincter due to atrophy and fibrous replacement of the esophageal muscularis.

This can result in gastroesophageal reflux disease, or GERD, which is when the content of the stomach flows up to the esophagus and damages it.

Due to stomach acid irritating the normal esophageal mucosa, Barrett's esophagus can develop, which is when the normal stratified squamous epithelium of the esophagus transforms into simple columnar epithelium with interspersed goblet cells, like the ones normally found in the small and large intestine.

This is high yield because it can lead to esophageal adenocarcinoma.

Chronic damage and fibrosis to the esophagus can cause stricture formation.

The intestines can also be involved, which leads to malabsorption, and malabsorption to anemia due to iron deficiency.

Sources
  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Diagnosis and Classification of Systemic Sclerosis" Clinical Reviews in Allergy & Immunology (2010)
  3. "Cellular and molecular mechanisms in the pathophysiology of systemic sclerosis" Pathologie Biologie (2015)
  4. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  5. "Systemic sclerosis/scleroderma: a treatable multisystem disease" Am Fam Physician (2008)
  6. "Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis" Annals of Internal Medicine (2004)
  7. "The'CREST'Syndrome" Archives of Internal Medicine (1979)
  8. "New therapeutic strategies for systemic sclerosis--a critical analysis of the literature" Clin Dev Immunol (2005)