OTHER DISORDERS! Adrian H Kendrick

Transcription

1 OTHER DISORDERS! Adrian H Kendrick

2 CONNECTIVE TISSUE DISORDERS

3 Connective Tissue Disease Connective tissue is - any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs. composed of two major structural protein molecules: collagen and elastin. In connective tissue disease - collagen and elastin become injured by inflammation. There may be abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one's own body tissues (autoimmunity).

4 Auto-immune disorders The classic collagen vascular diseases include: Systemic lupus erythematosus (SLE) An inflammation of the connective tissues, SLE can afflict every organ system. It is up to 9x more common in women than men and strikes black women 3x as often as white women. The condition is aggravated by sunlight. Rheumatoid arthritis Systemic disorder in which immune cells attack and inflame the membrane around joints. It can affect the heart, lungs, and eyes.

5 Auto-immune disorders The classic collagen vascular diseases include: Scleroderma an activation of immune cells that produces scar tissue in the skin, internal organs, and small blood vessels. Affects women 3x more often than men overall, but increases to a rate 15x times greater for women during childbearing years More common among black women.

6 Auto-immune disorders The classic collagen vascular diseases include: Sjögren's syndrome (Sjögren's disease) chronic, slowly progressing inability to secrete saliva and tears. Can occur alone or with rheumatoid arthritis, scleroderma, or systemic lupus erythematosus. Nine out of 10 cases occur in women, most often at or around mid-life.

7 Auto-immune disorders The classic collagen vascular diseases include: Mixed connective tissue disease features of various connective-tissue diseases such as systemic lupus erythematosus ;; systemic sclerosis;; dermatomyositis;; polymyositis and occasionally, Sjögren syndrome can coexist and overlap. The course of the disease is chronic and usually milder than other CTDs. In most cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or Scleroderma.

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9 General Pattern Restrictive ventilatory defect Reduced FVC and FEV 1 normal PEF Reduced TLC TLco reduced and may reflect Interstitial lung disease Pulmonary vascular abnormalities Respiratory muscle weakness Pleural and ribcage abnormalities

10 Rheumatoid Arthritis Pleural effusions and pleural thickening occurs Restrictive ventilatory defect Disproportionally reduced TLco and Kco P I,max may be reduced? steroid use. In the absence of overt respiratory disease TLco or VC Mild reduction in lung volumes observed due to musculoskeletal abnormalities or to pleural thickening

11 Systemic Sclerosis Interstitial lung disease Pulmonary hypertension VC and TLco SpO 2 on exercise related to VC VO 2,peak, AaPO 2 and V D /V T

12 Systemic Lupus Erythematosus Pleural effusions & pleural thickening common Occasional occurrences Acute lupus pneumonitis Alveolar haemorrhage Pulmonary vascular disease Pulmonary hypertension Shrinking Lung Syndrome VC and TLco -?Kco VO 2,peak

13 Shrinking Lung Syndrome? Due to diaphragm dysfunction?myopathy h.com/articles/vol4iss2/domingolung-jar-spring.pdf

14 Mixed Connective Tissue Disease Classified on basis of immunological features VC and TLco

15 Sjögren s Syndrome Airway and alveolar dysfunction observed FEV 1 and FEV 1 %FVC More common - RV/TLC ratio In ILD - TLco

16 HERITABLE DISORDERS

17 Genetic (Inherited) Lung Diseases Inherited Disorders Cystic fibrosis Alpha-1-antitrypsin Primary ciliary dyskinesia Kartagener s syndrome Marfan s syndrome Ehlers-Danlos syndrome Congenital Metabolic Problems Mucopolysaccaridosis Nieman-Pick disease Riley-Day syndrome* Gauchers Disease *Referred to as Familial dysautonomia subsequently

18 Heritable Disorders Marfan syndrome genetic disease causing abnormal fibrillin. Ehlers-Danlos syndrome causes progressive deterioration of collagens, with different EDS types affecting different sites in the body, such as joints, heart valves, organ walls, arterial walls Osteogenesis imperfecta (brittle bone disease) caused by insufficient production of good quality collagen to produce healthy, strong bones. Stickler syndrome affects collagen, and may result in distinctive facial appearance, eye abnormalities, hearing loss, and joint problems.

19 MARFAN S SYNDROME

20 Marfan s Syndrome This is a genetic disorder of human connective tissue. It may range from mild to severe The most serious complications are defects of the heart valves and aorta, often leading to an early death. The syndrome also may affect the lungs, eyes, dural sac surrounding the spinal cord, the skeleton, and the hard palate. People with Marfan tend to be unusually tall, with long limbs and long, thin fingers.

21 Marfan syndrome is caused by mutations in the gene encoding fibrillin-1, an important component of microfibrils in the extracellular matrix surrounding myofibres. Fibrillin-1 seizes TGF- via an interaction with latent TGF- binding proteins (LTBP). Mutations in fibrillin-1 lead to elevated levels of TGF-, which blocks activation of satellite cells preventing them from proliferating and fusing into damaged myofibres to regenerate the muscle cells. A key regulator of latent TGF- activation is thrombospondin-1 (Tsp-1), which is produced in response to activation of the angiotensin II type 1 receptor (AT1) by angiotensin (AT).

22 Marfan s Syndrome In addition to providing structural support, the normal fibrillin-1 protein also contributes to cell signaling activity, binding to the protein transforming growth factor beta (TGF-β). Mis-regulated TGF-β has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. It is also possible that excessive TGF-β at the lungs, heart valves, and aorta weakens the tissues and causes the features of Marfan syndrome.

23 Genetics The disease is an autosomal dominant disorder (D), Offspring who inherit only one copy of the Marfan gene from either parent will develop Marfan syndrome and be able to transmit it to their children.

24 Sign s & Symptoms More than 30 different signs and symptoms are variably associated with Marfan syndrome. The most prominent of these, affecting the skeletal system, are found in numerous other diseases It is not possible to diagnose Marfan syndrome based on the patient s appearance. Instead, distinguishing Marfan syndrome from other "marfanoid" syndromes (without recourse to DNA testing) requires the assessment of non-skeletal clinical and laboratory findings, especially of the eyes, aorta, and heart. To complicate the physical assessment, considerable clinical variability occurs even within families carrying an identical DNA variant.

25 Sign s & Symptoms - Skeletal system Most of the readily visible signs are associated with the skeletal system. Many individuals grow to above-average height. Some have long, slender limbs with long fingers and toes An individual's arms may be disproportionately long, with thin, weak wrists.

26 Sign s & Symptoms - Skeletal system Abnormal curvature of the spine (scoliosis), Abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum is not uncommon. Other signs include abnormal joint flexibility, a high palate, flat feet, hammer toes, stooped shoulders, and unexplained stretch marks on the skin.

27 Sign s & Symptoms - Cardiovascular system The most serious signs and symptoms associated with Marfan syndrome involve the cardiovascular system: Excessive fatigue, shortness of breath, heart palpitations, racing heartbeats, or angina pectoris with pain radiating to the back, shoulder, or arm. Cold arms, hands and feet can also be linked to Marfan syndrome because of inadequate circulation. A heart murmur, or symptoms of angina can indicate further investigation. The signs of regurgitation from prolapse of the mitral or aortic valves result from cystic medial degeneration of the valves, which is commonly associated with Marfan syndrome.

28 Sign s & Symptoms - Cardiovascular system However, the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue in the ascending aorta causes an aortic aneurysm or aortic dissection An aortic dissection is most often fatal and presents with pain radiating down the back, giving a tearing sensation.

29 Sign s & Symptoms - Cardiovascular system

30 Sign s & Symptoms - Cardiovascular system

31 Sign s & Symptoms - Cardiovascular system

32 Chest X-ray

33 Sign s & Symptoms - Lungs Pulmonary symptoms are not a major feature of Marfan syndrome, but spontaneous pneumothorax is common. In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the pleural space between the chest wall and a lung. The lung becomes partially compressed or collapsed resulting in pain, shortness of breath, cyanosis, and, if not treated, it can cause death. Other possible pulmonary manifestations of Marfan syndrome include sleep apnoea and idiopathic obstructive lung disease. Pathologic changes in the lungs have been described such as cystic changes, emphysema, pneumonia, bronchiectasis, bullae, apical fibrosis and congenital malformations such as middle lobe hypoplasia

34 Prognosis 40 years ago, Marfan syndrome patients faced a virtually hopeless situation due to chronic mitral and aortic regurgitation, heart failure, and acute and chronic aortic dissection. Their life span was reduced by at least one third, with many patients dying in the second and third decades. Currently, cardiovascular manifestations of Marfan syndrome remain among the central issues in diagnosis and management of these patients, Physicians who manage these patients need to reassure them that with monitoring and current therapies, a nearly normal life expectancy can be attained

35 Management There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades and is now similar to that of the average person. Clinical trials are also under way for promising new treatments. Currently, the syndrome is treated by simply addressing each issue as it arises and, in particular, preventative medication even for young children to slow progression of aortic dilation if such exists.

36 Management Marfan syndrome is expressed dominantly. This means a child with one parent a bearer of the gene has a 50% probability of getting the syndrome. However, as the gene causing Marfan syndrome is known, arduous genetic techniques are able to circumvent this. In 1996, the first preimplantation genetic testing therapy for Marfan was conducted;; in essence PGT means conducting a genetic testing on early stage IVF embryo cells and discarding those embryos affected by the Marfan mutation.

37 Management Regular check-ups by a cardiologist are needed to monitor the health of the heart valves and the aorta. The goal of treatment is to slow the progression of aortic dilation and damage to heart valves by eliminating arrythmias, minimizing the heart rate, and minimizing blood pressure. Beta blockers have been used to control arrythmias and slow the heart rate. Other medications might be needed to further minimize blood pressure without slowing the heart rate, such as ACE inhibitors and angiotensin II receptor antagonists. If the dilation of the aorta progresses to a significant diameter aneurysm, causes a dissection or a rupture, or leads to failure of the aortic or other valve, then surgery (possibly a composite aortic valve graft or valve-sparing aortic root replacement) becomes necessary.

38 Management Although aortic graft surgery (or any vascular surgery) is a serious undertaking it is generally successful if undertaken on an elective basis. Surgery in the setting of acute aortic dissection or rupture is considerably more problematic. Elective aortic valve/graft surgery is usually considered when aortic root diameter reaches 50 mm (2.0 inches), but each case needs to be specifically evaluated by a qualified cardiologist. New valve-sparing surgical techniques are becoming more common. As Marfan patients live longer, other vascular repairs are becoming more common, e.g., repairs of descending thoracic aortic aneurysms and aneurysms of vessels other than the aorta.

39 Famous people with Marfan syndrome Flo Hyman Volleyball Vincent Schiavelli Actor Mary, Queen of Scots Osama bin Laden 196cm 193cm 180cm 196cm

40 Inherited Disorders Marfan s Syndrome Very tall Chest wall and lungs affected TLco low normal VO 2,max deconditioning High prevalence of OSA

41 EHLERS-DANLOS SYNDROME

42 Ehlers-Danlos syndrome - Overview This is an inherited connective tissue disorder with different presentations depending of the classification It is caused by a defect in the structure, production, or processing of collagen or proteins that interact with collagen, such as mutations in the COL5A or COL3A genes.

43 Ehlers-Danlos syndrome - Overview Role of Collagen Collagen in connective tissue helps tissues resist deformation and is important in terms of the physical strength of skin, joints, muscles, ligaments, blood vessels and visceral organs Abnormal collagen results in these structures being more elastic.

44 EDS - Classification

45 EDS Skin and Joints

46 EDS - Kyphoscoliosis

47 EDS - Management There is no cure for Ehlers Danlos Syndrome - treatment is palliative. Close monitoring of the cardiovascular system, physiotherapy, occupational therapy, and orthopaedic instruments - wheelchairs, bracing, casting may be helpful. Activities that cause the joint to lock or overextend should be avoided.

48 EDS - Management A physiotherapist or occupational therapist to help strengthen muscles and teach patients how to properly use and preserve their joints. This may include - Aquatic therapy to promote muscular development and coordination Manual therapy, to gently mobilize the joint within the range of motion and/or manipulations Electrotherapy such as transcutaneous electrical nerve stimulation may help reduce local musculoskeletal pain.

49 EDS - Management Surgical repair of joints may be necessary at some point. Medication to decrease pain or manage cardiac, digestive, or other related conditions may be prescribed. To decrease bruising and improve wound healing, some patients have responded to ascorbic acid (Vitamin C). In general, medical intervention is limited to symptomatic therapy. Prior to pregnancy, patients with EDS should have genetic counselling.

50 EDS - Management Children with EDS should be provided with information about the disorder, so they can understand why contact sports and certain other physically stressful activities should be avoided. Children should be taught that demonstrating the unusual positions they can maintain due to loose joints should not be done as this may cause early degeneration of the joints. Patients may find it hard to cope, so emotional support and behavioural and psychological therapy may be required Family members, teachers and friends must be provided with information about EDS so they can accept and assist the child as necessary.

51 EDS Lung Function

52 EDS Lung Function

53 EDS Sleep Disordered Breathing Sleep-Disordered Breathing in Ehlers-Danlos Syndrome: A Genetic Model of OSA. Christian Guilleminault;; Michelle Primeau;; Hsiao-yean Chiu;; Kin Min Yuen;; Damien Leger;; Arnaud Metlaine. Chest. 2013;; 144: Objectives: The objective of this study was to investigate the presence of sleep-disordered breathing (SDB) in patients with Ehlers-Danlos syndrome. Ehlers-Danlos syndrome is a genetic disorder characterized by cartilaginous defects, including nasalmaxillary cartilages. Methods: A retrospective series of 34 patients with Ehlers-Danlos syndrome and complaints of fatigue and poor sleep were evaluated by clinical history, physical examination, polysomnography (PSG), and, in some cases, anterior rhinomanometry. Additionally, a prospective clinical investigation of nine patients with Ehlers-Danlos syndrome was performed in a specialized Ehlers-Danlos syndrome clinic. Results: All patients with Ehlers-Danlos syndrome evaluated had SDB on PSG. In addition to apnoeas and hypopneas, SDB included flow limitation. With increasing age, flow limitation decreased in favour of apnoea and hypopnea events, but clinical complaints were similar independent of the type of PSG finding. In the subgroup of patients who underwent nasal rhinomanometry, increased nasal resistance was increased relative to normative values. Nasal CPAP improved symptoms. Patients with Ehlers- Danlos syndrome presenting to the medical clinic had symptoms and clinical signs of SDB, but they were never referred for evaluation of SDB. Conclusions: In patients with Ehlers-Danlos syndrome, abnormal breathing during sleep is commonly unrecognized and is responsible for daytime fatigue and poor sleep. These patients are at particular risk for SDB because of genetically related cartilage defects that lead to the development of facial structures known to cause SDB. Ehlers-Danlos syndrome may be a genetic model for OSA because of abnormalities in oral-facial growth. Early recognition of SDB may allow treatment with orthodontics and myofacial re-education.

54 EDS - Prognosis EDS is a lifelong condition. The outlook for individuals with EDS depends on the type of EDS Symptoms vary in severity, even within one sub-type, and the frequency of complications changes on an individual basis. Some individuals have negligible symptoms while others are severely restricted in their daily life. Extreme joint instability, chronic musculoskeletal pain, degenerative joint disease, frequent injuries, and spinal deformities may limit a person's mobility. Severe spinal deformities will probably have sleep-breathing problems.

55 EDS - Prognosis In extreme joint instability, dislocations may occur from simple tasks such as rolling over in bed or turning a doorknob. Secondary conditions such as autonomic dysfunction or cardiovascular problems, occurring in any type, can affect prognosis and quality of life. Severe mobility-related disability is seen more often in Hypermobility-type than in Classical-type or Vascular-type. Although all types are potentially life-threatening, the majority of individuals will have a normal lifespan. However, those with blood vessel fragility have a high risk of fatal complications, with arterial rupture is the most common cause of sudden death in EDS. Spontaneous arterial rupture most often occurs in the second or third decade, but can occur at any time. The median life-expectancy within the population with Vascular EDS is 48 years.

56 Famous People with EDS Cherylee Houston Myleene Class Russell Kane

57 A WEIGHTY PROBLEM

58 Obesity More Fries!

59 Obesity Major clinical issue 25% of adult population in UK clinically obese. Children catching up. Results in a restrictive ventilatory defect with low TLco and raised Kco. High incidence of OSA and OHVS in such patients leading to treatment with CPAP (OSA) or NIV (OHS) Check ESS in clinic but normal ESS does not exclude OSA!

60 Lung Volumes

61 Summary Connective tissue disorders generally result in - Restrictive Ventilatory Defects are common Most useful lung function test Kco Obesity Major issue and getting bigger! Restrictive defect particularly at BMI > 35 kg.m -2 Check for OSA and OHVS