Take home points: October 2015

Childhood mastocytosis: Update

  • Cutaneous mastocytosis in children is the most common form of mastocytosis
  • True systemic mastocytosis is very rare in children
  • An NIH study of 105 children found 30-65% improved over time
  • Elevated baseline tryptase level and organ swelling were good indicators of SM
  • Serum tryptase should be measured every 6-12 months
  • Children with swelling of both liver and spleen were positive for CKIT D816V mutation
  • Swelling of liver and spleen together was linked to disease persisting into adulthood
  • Most children with UP with skin and minor GI issues had normal tryptase
  • Diffuse cutaneous mastocytosis patients had a much higher average tryptase but no organ swelling
  • Serum tryptase and IgE were inversely related (high tryptase with low IgE, low tryptase with high IgE)

Chronic mast cell leukemia: a new variant of systemic mastocytosis

  • Mast cell leukemia (MCL) has a significantly shortened lifespan
  • Usually over 20% of nucleated cells in bone marrow are atypical mast cells
  • Mast cells are present in large quantities on the blood
  • Cases where less than 10% of white blood cells in blood are mast cells are called aleukemic variant MCL
  • Cases where over 20% of nucleated cells in bone marrow are mature mast cells are called chronic MCL
  • Chronic MCL patients do not have any C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Chronic MCL patients have stable disease state but can progress to acute MCL at any time
  • Mediator release symptoms are more common in chronic MCL than acute MCL
  • Acute MCL is marked by immature CD25+ mast cells
  • Acute MCL patients do have C findings (the clinical markers for SM patients associated with very aggressive disease)
  • Acute MCL has a very short survival time, usually less than a year

Take home points: August 2015

Gastroparesis: Part 1

  • GP is a condition in which stomach contents do not move into the small intestine in an appropriate time frame without an obvious anatomical reason
  • GP patients can have severe symptoms, including nausea, vomiting, abdominal pain and bloating
  • GP can be episodic or chronic
  • The degree of gastric emptying delay does not impact symptom severity
  • GP may affect up to 2% of the population
  • GP is increasing over the last twenty years with no clear reason as to why
  • Cisapride is effective for treating GP but was removed from the market
  • GP symptoms are generic and make the cause hard to identify
  • Idiopathic GP has no clear cause and affects up to 1/3 of GP patients

Gastroparesis: Treatment (Part 2)

  • Treating dehydration and electrolyte and nutritional deficiencies are key to initial GP management
  • 64% of GP patients do not consume enough daily calories
  • Vitamins A, B6, C and K, iron, potassium and zinc are often deficient in GP patients
  • Small meals with low fat and fiber are recommended
  • Liquids or blended solids often empty normally from stomach
  • Feeding tubes may be placed if malnutrition is significant
  • Metoclopramide is approved for GP but use longer than twelve weeks carries risks like dystonia
  • Domperidone is not approved in US for GP but can be imported through a special FDA program for GP
  • Medications to increase gastric motility, like erythromycin, are often used
  • Medications for nausea and vomiting are common, such as ondansetron, scopolamine, draonabinol and tricyclic antidepressions
  • Nortriptyline and desipramine are tricyclics of choice as amitryptline can cause delayed gastric emptying
  • Opiates can induce GP so meds like gabapentin, tramadol, tapentadol, pregabalin and nortriptyline are preferred for abdominal pain
  • Botox injection into pyloric sphincter can increase gastric emptying but doesn’t always improve symptoms
  • Acupuncture and gastric pacemaker are also options

Gastroparesis: Diabetes and gastroparesis (Part 3)

  • 40% of patients with type I diabetes have delayed gastric emptying
  • 20% of patients with type II diabetes have delayed gastric emptying
  • In 2004, 26.7% of GP patients had diabetes
  • Diabetic patients with GP are more likely to have nausa and vomiting as predominant symptoms
  • GP can hinder effective blood sugar management
  • High blood sugar is associated with GP and vagus nerve damage
  • Gastric electric stimulation (gastric pacemaker) works better when GP is caused by diabetes than GP from other causes
  • Effective GP management improves blood sugar management and A1C level

Gastroparesis: Post-surgical gastroparesis (Part Four)

  • Surgery is a common trigger for GP
  • Surgeries that manipulate the stomach are more associated with GP, like gastrectomy, fundoplication or weight loss surgery
  • Gastric inflammation associated with surgery inhibits GI motility
  • 7.2% of GP cases occur after gastrectomy or fundoplication
  • Nissen fundoplication is the most common cause of post-surgical GP
  • A follow up surgery after Nissen fundoplication can sometimes reverse GP
  • Surgeries that don’t manipulate the stomach can also cause GP, like removal of esophagus, lung transplant, and liver surgery

Gastroparesis: Less common causes (Part Five)

  • Parkinson disease, multiple sclerosis, muscular dystrophy, myopathy, scleroderma, Sjogrens, polymyositis and stroke can all cause GP.
  • 10.8% of GP cases are associated with connective tissue disorder
  • Pseudo obstruction syndromes and autonomic neuropathy can occur concurrently with GP
  • Viral infections can cause acute GP that usually resolves within a year
  • Spinal cord injury, hypothyroidism, hyperparathyroidism, Addison’s disease and use of opiates or anticholinergics can contribute to GP
  • GP occurs disproportionately in people who have had their gallbladders removed
    • Often, GP does not immediately follow gallbladder removal but can present months or years later
    • Gallbladder removal is also associated with conditions that can occur with GP such as chronic fatigue syndrome, fibromyalgia, depression and anxiety
    • GP patients who have had gallbladders removed are usually older women who are overweight despite not coming enough calories

Take home points: September 2015

Naturally occurring mast cell stabilizers: Part 1

Naturally occurring mast cell stabilizers: Part 2

Naturally occurring mast cell stabilizers: Part 3

Naturally occurring mast cell stabilizers: Part 4

Amentoflavone Ginkgo biloba, St. John’s Wort Decreases histamine release
Artekeiskeanol A Artemisa keiskeana May treat arthritis

Decreases mast cell degranulation

Decreases production of IL-13 and TNF

Curcimin Turmeric Decreases degranulation

Decreases production of IL-4 and TNF

Ellagic acid Strawberries, raspberries, pomegranate, walnuts Suppresses IgE activation

Decreases release of histamine, TNF, IL-6

Emodin Rhubarb, frangula bark Decreases IgE degranulation

Decreases IgE triggered production of TNF, PGD2, LTC4

Decreases secretion of TNF and IL-6

Epigallocatechin gallate White and green teas, apples, onions, hazelnuts Decreases degranulation

Decreases LTC4 secretion

Fisetin Apples, onions, persimmon, strawberries, cucumber Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-1b, IL-6, IL-8 and TNF

Decreased action of NF-kB, decreased mediator production

Furanocoumarin from Angelica dahurica Angelica dahurica Inhibits COX-2 and 5-LO, decreasing production of prostaglandins and LTC4
Genistein Genista tinctoria Decreases IgE degranulation

Decreases histamine release

Nature tyrosine kinase inhibitor

Ginkgetin Gingko biloba Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes
Gnetin H Paeonia aneomala Resveratrol derived polymer

Decreases mast cell degranulation

Effective at lower dose than reservatrol

Decreases histamine secretion

Decreases production of TNF, IL-4, COX-2 and PGE2

Homoisoflavonone Cremastra appendiculata Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes

Decreases IgE triggered production of TNF and IL-6

Honokiol Magnolia obovata Suppresses allergic response and basophil activation
Hydroxytyrosol Olive oil, olive leaves Inhibited activation of mast cells at high concentration
Hypothemycin Hypomyces mushrooms Interfere with activation of CKIT and IgE receptors, inhibiting mast cell activation

 

Decreases production of IL-4

Kaempferol Potatoes, squash, cucumbers, peaches, Aloe versa Decreases IgE degranulation

Decreased IgE triggered histamine release

Affects estrogen signaling

Luteolin Celery, carrots, chamomile tea Prophylactic use of luteolin suppresses activation of mast cells and T cells

Decreases IgE degranulation

Decreases production of mediators

Magnolol Magnolia obovata Suppresses allergic response and basophil activation
Morin Osage orange, guava Decreases mast cell degranulation

Decreases IgE activation

Myricetin Walnuts, onions, red grapes Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-6 and TNF

Decreased action of NF-kB, decreased mediator production

Polydatin Resveratrol precursor

Makes small intestine mucosa less “leaky” and inhibited allergic reaction in intestines

Decreases degranulation by up to 65%

Decreases histamine in intestinal mucosa and serum

Decreases production of IL-4

Quercetin Red onion, sweet potato, kale Inhibits production of histamine, prostaglandins, leukotrienes, IL-1b, IL-6, IL-8 and TNF
Resveratrol Grapes, raspberries, blueberries, peanuts Directly interferes with degranulation

Decreases production of TNF, IL-6 and IL-8

Rottlerin Mallotus philippensis Decreases degranulation of airway mast cells

Decreases histamine release

Suppresses IgE activation

Rutin Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-1b, IL-6, IL-8 and TNF

Decreased action of NF-kB, decreased mediator production

Scopoletin Stinging nettle, Japanese belladonna, chicory, passion flower Decreases production of TNF, IL-6, IL-8

Inhibits NF-kB, affecting mediator production

Selinidin Angelia keiskei Inhibits IgE degranulation

Decreases production of LTC4 and TNF

Substance Source Function
Thunberginol A Hydrangeae macrophylla Decreases histamine release

Decreases production of TNF and IL-4

Thunberginol B Hydrangeae macrophylla Decreases degranulation from IgE or other sources

Decreases IgE triggered production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF

Xanthones from purple mangosteen Garcinia mangostana Decreases release of histamine, PGD2, LTC4 and IL-6

 

Role of sex hormones in hereditary angioedema

Gastroparesis: Autonomic nervous system and vagus nerve (Part Six)

  • ANS controls many involuntary functions including digestion and therefore gastric emptying
  • The vagus nerve coordinates gastric motility
  • ANS dysfunction inhibits digestion and motility
  • GP is common in patients with ANS conditions, like POTS
  • Treatment of autonomic dysfunction (as in POTS) can sometimes improve GP
  • Damage to the vagus nerve can cause liquids to move rapidly out of the stomach while solids are retained
  • Surgery and high blood sugar can damage the vagus nerve
  • In GP patients, nerve cells are not shaped correctly
  • 83% of GP patients have abnormalities in their stomach biopsies

Gastroparesis: Idiopathic gastroparesis (Part Seven)

  • 35-67% of GP cases are idiopathic (IGP)
  • IGP affects three times more women than men, especially young and middle-aged women
  • IGP is more likely in young women who are overweight or obese
  • Moderate to severe abdominal pain was more frequent in IGP than other types
  • Nausea, abdominal pain, vomiting, bloating and feeling full are common in IGP
  • Medications that may be helpful but need investigation include sildenafil, paroxetine, cisapride, tegaserod, clonidine and buspirone

Take home points: July 2015

Mast cell interactions with B and T cells
• Mast cells communicate with other cells by:
o Releasing chemicals to tell another cell to do something
o Other cells releasing chemicals to tell mast cells to do something
o Moving right up against other cells, which allows the cells to “talk”
• B cells are white blood cells that make antibodies and protect against infections.
o Mast cells can tell B cells to make IgE, an allergy antibody.
o When mast cells touch B cells, the mast cells can release IL-6 which tells B cells to live longer.
o Mast cells can tell B cells to make IgA, an antibody.
• T cells are white blood cells that have many functions.
o T cells and mast cells are found close together in many inflammatory conditions, like ulcerative colitis.
o Activated T cells can activate mast cells.
o Mast cells can tell T cells to proliferate and produce inflammatory molecules.
o A kind of T cell called Treg (T reg, like in regulatory) cells can make mast cells harder to activate and interfere with degranulation.

Mast cells in kidney disease
• Kidney disease is often not identified until 60-70% of functional kidney cells have been damaged beyond repair.
• Mast cells are rare in healthy kidneys.
o Damaged kidneys can have up to 60x the normal amount of mast cells.
o Mast cell count is not related to disease severity.
• Atopic disease, like atopic dermatitis and allergic asthma, is linked to idiopathic nephrotic disease, kidney disease of unknown origin.
o The nephrotic disease and atopic disease could be manifestations of the same overarching condition.
o In patients with both, IgE levels are high.
• Tryptase is elevated in some patients with kidney damage.
• Mast cells are responsible for bringing other inflammatory cells to the damaged kidney.
• Mast cells can cause fibrosis in kidneys.
• In some roles, mast cells can protect kidneys from damage.

Regulation of mast cells by IgE and stem cell factor (SCF)
• Mast cells are mostly regulated in two ways
• IgE binds to the IgE receptor (FceRI) on mast cells and activates them
o Activation by IgE results in degranulation and secretion of mediators
o IgE induces mediator release by affecting the amount of calcium inside mast cells
• Stem cell factor (SCF) binds to the CKIT receptor on mast cells and tells them to stay alive
o SCF also increases degranulation and production of cytokines
o SCF helps mast cells to adhere to other cells

Mast cells in vascular disease: Part 3
• Mast cells are involved in the formation and growth of aneurysms
• Activated mast cell populations are increased in vessels that rupture
• Chymase, a mast cell mediator, can degrade vessels and increase risk of rupture
• Leukotrienes contribute to aneurysm formation