Download - Thyroid function affects the muscle, joints and bone ... - USJ

Presentation Summary:

Thyroid function affects the muscle, joints and bone health.

Hypothyroidism induces a metabolic myopathy and therefore a wide spectrum of symptoms related to

muscle impairment. Hypothyroid arthropathy involves most commonly the knees, hands and wrists and is

characterized by non-inflammatory effusions.

Hyperthyroidism is one of the secondary causes of osteoporosis, as it induces bone resorption, a negative

calcium balance, and yields an increased fracture risk. Thyroid acropatchy is associated with auto-

immune thyroid disease and manifests as clubbing and swelling of the fingers and toes, and rarely affects

distal joints.

Finally, new biologic therapies for rheumatic diseases, such as adalimumab, were recently found to be

associated with subacute thyroiridtis.

Musculo-skeletal Manifestations of Thyroid Disorders

Marlene Chakhtoura, MD, MScAssistant Professor of Medicine

Calcium Metabolism & Osteoporosis Program

American University of Beirut-Medical Center

Prevalence of Hypothyroidism Worldwide

Taylor Nat Rev Endo 2018

Prevalence of overt hypothyroidism in the general population Europe: 0.2% - 4.2% USA : 0.3% - 3.7% (depending on the definition used and population studied)

Countries in white represent no data available

Prevalence of Hyperthyroidism Worldwide


A meta-analysis of European studies estimated a mean prevalence rate of 0.75% for males and females combined and an incidence rate of 51 cases per 100,000 per year

Countries in white represent no data available

Risk factors for Thyroid Dysfunction

Risk factor Hypothyroidism Hyperthyroidism

Female sex + +

Iodine deficiency or excess + +

Auto-immune diseases + +

Genetic risk factors + +

Selenium deficiency + +

Drugs + +

Smoking - +

Alcohol - NA


(-) reduced risk; (+) increased risk

What is the risk of thyroid dysfunction in rheumatologic diseases?

Thyroid Auto-immunity and Rheumatoid Arthritis

Pan Endocrine 2015

Systematic review and meta-analysis until 201413 Case control studies

TgAb: Thyroglobulin antibody; TPOAb: Anti-peroxidase antibodies

Thyroid Disorders and Systemic Lupus Erythematosus

-Systematic review and meta-analysis -Search until 2017-Observational studies on thyroid dysfunction and SLE (ACR criteria)-10 studies, both genders -Mean age 26-50 y

Thyroid dysfunction N of studies

OR (SLE vs control)

Hypothyroidism 8 2.93 (95% CI, 1.81–4.75)

Subclinicalhypothyroidism

5 5.67 (95% CI, 3.50– 9.18)

Hyperthyroidism 9 Non significant

Subclinical hyperthyroidism

4 Non significant

Luo Lupus 2018

Outline

• Thyroid hormones and the musculo-skeletal system

• Thyroid Myopathy

• Thyroid Arthropathy and Acropachy

• Osteoporosis • Subclinical and clinical thyroid disease

• Subacute thyroiditis

• Take home messages

Thyroid hormones and the musculo-skeletal system

Role of T3:-Regulates glucose uptake (GLUT4)-Stimulates oxidative pathways by increasing mitochondrial biogenesis and oxygen consumption-Regulates non-enzyme coding genes involved in muscle function-Involved in myogenesis and muscle differentiation -Connective tissue metabolism (GAG)

Sindoni Rev Endocr Metab Disord 2016; Bloise J Endo 2018

Skeletal muscle

Thyroid hormones and the musculo-skeletal system

Bassett Endocr Rev 2013

Is mediated by specific membrane transporter proteins, including monocarboxylate transporter (MCT) 8 and MCT10, the organic anion transporter protein-1c1 (OATP1c1), and the nonspecific L-type amino acid transporters 1 and 2 (LAT1, LAT2)

Outline







Hypothyroid Myopathy

• Prevalence 20-80% in retrospective studies

• Myopathy may precede biochemical hypothyroidism or occur simultaneously

• Usually proximal myopathy, rarely axial and pelvic muscle involvement, typical of polymyositis

• Elevated CK 57-90%

• Serum CK values correlated positively with serum TSH and negatively with serum FT3 and FT4, and therefore correlated with the severity of biochemical hypothyroidism, but not with the clinical severity of the muscular symptoms.

Sindoni Rev Endocr Metab Disord 2016

Hypothyroid Myopathy

Presentation Definition

Asymptomatic hyper-CKemia Persistent and asymptomatic high serum creatine kinase (CK)

Myalgia Muscle pain (Painful cramps, fatigue and exercise-intolerance)

Myoedema Mounding of muscle tissue after finger pressure

Muscular pseudohypertrophy

Increased muscle volume not related to muscle fiber hypertrophy

Proximal myopathy Symmetrical weakness of proximal upper and/or lower limbs

Rhabdomyolysis Massive and acute muscle fiber lysismassive pain and weakness

Rare syndromes Acute compartment syndromeHoffman’s syndromeKoche – Debre’ – semelaigne syndrome

Sindoni Rev Endocr Metab Disord 2016

Hypothyroid Myopathy Diagnosis:• Electromyography (EMG) can demonstrate low/small amplitude potentials

which could help with diagnosis. • Normal in 50% of the patients and does not preclude the diagnosis

Treatment:• Thyroid hormone replacement restoration of normal thyroid function,

gradual resolution of most neuromuscular symptoms is noted in most of the patients.

• CK levels fall quickly with thyroxine replacement with a few weeks and could resolve even before TSH comes to a normal range.

surrogate to monitor response to treatment in the initial stages• Myopathic symptoms can take up to 6 months to resolve.

Expert opinion to supplement by T4 and T3• Most of the symptoms resolve within a year of adequate hormone

replacement.Fariduddi StatPearls 2019

Myopathy in thyroid disease

Duyff J Neurol Neurosurg Psychiatry 2000

Prospective cohort Adults with newthyroid dysfunctionEvaluation:-Clinically-Dynamometry -Electrodiagnosis

Resolution in 79% at

6.9 (4) months

At 1 year, weakness

in 21%, confirmed in

13%

Resolution in ALL

at 3.6 (2.3)

months

Thyrotoxic Periodic Paralysis• Age 20-40 y; Men > Women; Asian> Western

• Presentation: recurrent, transient episodes of muscle weakness, mild to complete flaccid paralysis; proximal >distal

• Triggers: carbohydrates, alcohol, exercise

• Biochemical evidence of hyperthyroidism (Graves Disease being the most common) and hypokalemia (may be normal if during the recovery phase), and other electrolytes (Ph, Mg) imbalance

• Etiology: Increased Na/K-ATPase pump activity and number

• Treatment: K replacement and definitive treatment of thyroid disease

Kung JCEM 2006

Outline







Thyroid and Joint Disease

• Carpal tunnel syndrome

• Arthralgia and joint effusion

• Crystal deposition

• Thyroid Acropachy

Hypothyroidism and Carpal Tunnel

Shiri Muscle Nerve 2014

Carpal Tunnel diagnosed by nerve conduction assessment in the majority of the studies

Hypothyroid Arthropathy

• Predilection for epiphyseal involvement in hypothyroid individuals with secondary skeletal abnormalities (femoral head, tibial plateau, or digital phalanges)

• Characteristics of arthropathy:

• Non-inflammatory effusion

• Elevated synovial fluid viscosity

• Knee, hand, and wrist involvement

McLean Sem Arth Rheuma 1995

Hypothyroid Arthropathy

• Several bone and joint abnormalities have been described in hypothyroid patients:• Epiphyseal dysgenesis • Slipped capital femoral epiphysis• Aseptic necrosis • Erosive osteoarthritis• Gout and Pseudogout (to follow)

• Thyroid hormone replacement leads to clinical and a dramatic radiographic improvement


Hypothyroidism and Chondrocalcinosis


Few small studies assessed this associationAll had low power Problems in design (selection and assessment of the control group)

CC: chondrocalcinosis, PA: pyrophosphate arthropathy (PA)

Hypothyroidism and Gout

Study Results

Singh 2018Medicare database N = 1,572,874

Gout VS controls: HR of incident hypothyroidism 1.76 (1.72, 1.80)*

Bruderer 2017UK-based Clinical Practice Research DatalinkN=136,318

Hypothyroid VS euthyroid**:OR of gout 1.12 (95% CI 1.05–1.20)

LT4 replacement VS no replacement**:OR of gout 1.54 (95% CI 1.24–1.92)

No significant association with hyperthyroidism

Might be explained by the fact that thyroid hormones influence serum urate levels through regulation of GFR. Hypothyroidism whose kidney function was normal should not be at an increased risk of developing incident gout, although not confirmed in sub-group analysis

*adjusted for medications and co-morbidities; ** adjusted for BMI, smoking, alcohol, co-morbidities

Thyroid Acropachy

• Thyroid acropachy is one of the extrathyroidal manifestations of autoimmune thyroid disease, Graves Disease.

• Ophthalmopathy is almost always present with dermopathy.

• Acropachy is present in extreme forms of dermopathy and may present with clubbing and swelling of the fingers and toes, with or without periosteal reaction of the distal bones; more rarely, acropachy may present with articular manifestation of distal joints

Gul Arthritis Rheumatol 2016 Fatourechi JCEM 2002

Thyroid Acropachy• In a series of 40 patients with thyroid dermopathy associated with acropachy

Fatourechi JCEM 2002

Strong association with smoking

No specific treatment for acropachy of thyroid.Immunosuppressive therapy are directed at associated ophthalmopathy and dermopathy.

Outline







Hypothyroidism and Bone Health

• Hypothyroidism per se is unlikely to be related to fracture risk, whereas long term supraphysiological replacement with thyroid hormones may result in an increased risk of fracture

• Subclinical hypothyroidism and fracture/BMD: No association


Effect of excess thyroid hormones on bone

• Hyperthyroidism shortens the bone remodeling cycle

a high bone turnover state with increased bone resorption and formation rates (favoring more the former)

• The frequency of initiation of bone remodeling is also increased.

• The duration of bone formation and mineralization is reduced to a greater extent than the duration of bone resorption.

• This leads to reduced bone mineralization, a net 10% loss of bone per remodeling cycle, and osteoporosis


Subclinical hyperthyroidism and BMD

Individual participant data analysis systematic review

5,458 individuals (median age 72 years, 49.1% women), median follow-up of 6.7 years

Studies quality good to excellent

PROSPERO CRD42015019814; Segna JAMA Int Med 2018

Data adjusted for age, sex, body mass index (BMI), diabetes mellitus, smoking, and menopausal status.

Site N (SH/NL) Annualized %Δ BMD, vs euthyroid

Femoral Neck

283/4700 −0.18 (−0.34; −0.02) I2 0.0%

Total hip 232/4122 Non significant

Lumbar spine 163/2974 Non significant

Subclinical hyperthyroidism and BMD

Individual participant data analysis systematic review

5,458 individuals (median age 72 years, 49.1% women), median follow-up of 6.7 years

Shyper 5%

PROSPERO CRD42015019814; Segna JAMA Int Med 2018

Data adjusted for age, sex, body mass index (BMI), diabetes mellitus, smoking, and menopausal status.

Site N (SH/NL) Annualized %Δ BMD, vs euthyroid

Femoral Neck 283/4700 −0.18 (−0.34; −0.02) I2 0.0%

TSH < 0.1 54/4700 −0.59 (−0.99; −0.19) I2 0.0%

Exclusion of thyroid and bone active agents

184/3348 −0.36(−0.71; <−0.01) I2 45.9%

Age > 75 years - −0.34 (−0.52, −0.16)

In euthyroid, FN % %Δ BMD per year -0.59 (-0.63; -0.54)No effect of subclinical hypothyroidism on BMD

Subclinical hyperthyroidism and fracture

Individual particiapntsdata of 13 prospective cohorts

70 298 participants (median age 64 years; 61.3% women), a median follow-up of 12.1 years

Shyper 3%

Majority of studies were good quality

Data adjusted for age and sexSub-group analyses: trend for higher risk in men; no interaction with ageSensitivity analysis: Endogenous hyperthyroidism higher risk of hip, any and non-spine fracture No effect of subclinical hypothyroidism on fracture risk

Fracture Site N (SH/NL) HR, vs euthyroid

Hip 2082/56471 1.36 (1.13–1.64)6.0 vs 4.9 per 1000 person-years

Any fx 888/25901 1.28 (95% CI, 1.06–1.53)14.4 vs 11.2 per 1000 person-years)

Non spine fx 946/21722 Non significant

Spine fx 732/20328 Non significant

Blum JAMA 2015

TSH suppression for thyroid cancer and bone

Uzzan JCEM 1996

These results replicate findings from a previous systematic review and meta-analysis Faber et al 1994 showing that the effect of TSH suppression during LT4 treatment affects only BMD in postmenopausal women

Indications to treat in subclinical hyperthyroidism

ATA 2016

Hyperthyroidism and Osteoporosis

Systematic review and meta-analysisSearch until 200220 studies on BMD and 5 on fxGraves or toxic adenoma; All agesTreated medically or with radioactive iodine

Z-score comparing hyperthyroid to controlsFor the treated group, time since diagnosis 5-7 years Vestergaard Thyroid 2003



Z-score comparing hyperthyroid to controlsFor the treated group, time since diagnosis 5-7 years

Lumbar spine

Vestergaard Thyroid 2003

Hyperthyroidism and OsteoporosisSystematic review and meta-analysisSearch until 200220 studies on BMD and 5 on fxGraves or toxic adenoma; All agesTreated medically or with radioactive iodine

Z-score comparing hyperthyroid to controlsFor the treated group, time since diagnosis 5-7 years Vestergaard Thyroid 2003



Z-score comparing hyperthyroid to controlsFor the treated group, time since diagnosis 5-7 years

Hip fracture

Vestergaard Thyroid 2003

Secondary osteoporosis

AACE 2016

Effect of treatment of hyperthyroidism on bone health

• Case-control study from Denmark

• 124,655 with a fracture, matched for age and gender to 373,962 form the general population

Effect of surgery limited by the very small sample size (0.2% of the population) Vestergaard Calcif Tissue Int 2005

Outline







Thyroiditis Induced by Anti-rheumatic Drugs

Drug Case reports

Infliximab Ankylosing spondylitis (1 case)

Etanercept RA (2 cases); Juvenile idiopathic arthritis (1 case)

Adalimumab RA (1 case); Psoriatic arthritis (2 cases)

Rituximab Psoriatic arthritis (1 case)

www.PubMed.com (Sept 2019)

? Drug effect or viral thyroiditis with TNF- α inhibitors? Genetic predisposition Some describe drug withdrawal when thyroiditis was developed

http://www.pubmed.com/

Outline







Take home messages …

• Thyroid hormones have direct effects on the musculo-skeletal system.

• Hypothyroid myopathy is common and has a heterogeneous presentation.

• Thyroid hormone replacement drops CK levels but muscle symptoms may take up to 6 months.

• Thyroid dysfunction (deficiency or excess) can manifest as joint disease.

• Subclinical and clinical hyperthyroidism results in bone loss and increased fracture risk (hip and all fracture); Risk increases with age.

• Screening with TSH is recommended in patients with hyperthyroidism

• Cases of sub-acute thyroiditis have been reported on disease modifying anti-rheumatic drugs.

Thank you!