AMIODARONE EFFECTS ON THYROID FUNCTION

Amiodarone Effects on Thyroid Function

Amiodarone is a commonly used type III antiarrhythmic agent . It is structurally related to thyroid hormone and contains 39% iodine by weight. Thus, typical doses of amiodarone (200 mg/d) are associated with very high iodine intake, leading to greater than fortyfold increases in plasma and urinary iodine levels. Moreover, because amiodarone is stored in adipose tissue, high iodine levels persist for >6 months after discontinuation of the drug. Amiodarone inhibits deiodinase activity, and its metabolites function as weak antagonists of thyroid hormone action. Amiodarone has the following effects on thyroid function: (1) acute, transient suppression of thyroid function;

                              (2) hypothyroidism in patients susceptible to the inhibitory effects of a high iodine load; and               (3) thyrotoxicosis that may be caused by either a Jod-Basedow effect from the iodine load, in the setting of MNG or incipient Graves' disease, or a thyroiditis-like condition.

The initiation of amiodarone treatment is associated with a transient decrease of T4 levels, reflecting the inhibitory effect of iodine on T₄ release. Soon thereafter, most individuals escape from iodide-dependent suppression of the thyroid (Wolff-Chaikoff effect), and the inhibitory effects on deiodinase activity and thyroid hormone receptor action become predominant. These events lead to the following pattern of thyroid function tests: increased T₄, decreased T₃, increased rT₃, and a transient TSH increase . TSH levels normalize or are slightly suppressed within 1–3 months.

The incidence of hypothyroidism from amiodarone varies geographically, apparently correlating with iodine intake. Hypothyroidism occurs in up to 13% of amiodarone-treated patients in iodine-replete countries, such as the United States, but is less common (<6% incidence) in areas of lower iodine intake, such as Italy or Spain. The pathogenesis appears to involve an inability of the thyroid gland to escape from the Wolff-Chaikoff effect in autoimmune thyroiditis. Consequently, amiodarone-associated hypothyroidism is more common in women and individuals with positive TPO antibodies. It is usually unnecessary to discontinue amiodarone for this side effect, because levothyroxine can be used to normalize thyroid function. TSH levels should be monitored, because T4 levels are often increased for the reasons described above.

The management of amiodarone-induced thyrotoxicosis (AIT) is complicated by the fact that there are different causes of thyrotoxicosis and because the increased thyroid hormone levels exacerbate underlying arrhythmias and coronary artery disease. Amiodarone treatment causes thyrotoxicosis in 10% of patients living in areas of low iodine intake and in 2% of patients in regions of high iodine intake. There are two major forms of AIT, although some patients have features of both. 

Type 1 AIT is associated with an underlying thyroid abnormality (preclinical Graves' disease or nodular goiter). Thyroid hormone synthesis becomes excessive as a result of increased iodine exposure (Jod-Basedow phenomenon). 

Type 2 AIT occurs in individuals with no intrinsic thyroid abnormalities and is the result of drug-induced lysosomal activation leading to destructive thyroiditis with histiocyte accumulation in the thyroid; the incidence rises as cumulative amiodarone dosage increases. Mild forms of type 2 AIT can resolve spontaneously or can occasionally lead to hypothyroidism. Color-flow doppler thyroid scanning shows increased vascularity in type 1 AIT but decreased vascularity in type 2 AIT. Thyroid scintiscans are difficult to interpret in this setting because the high endogenous iodine levels diminish tracer uptake. However, the presence of normal or rarely increased uptake favors type 1 AIT.

In AIT, the drug should be stopped, if possible, although this is often impractical because of the underlying cardiac disorder. Discontinuation of amiodarone will not have an acute effect because of its storage and prolonged half-life. High doses of antithyroid drugs can be used in type 1 AIT but are often ineffective. In type 2 AIT, oral contrast agents, such as sodium ipodate (500 mg/d) or sodium tyropanoate (500 mg, 1–2 doses/d), rapidly reduce T4 and T₃ levels, decrease T₄  T₃ conversion, and may block tissue uptake of thyroid hormones. Potassium perchlorate, 200 mg every 6 h, has been used to reduce thyroidal iodide content. Perchlorate treatment has been associated with agranulocytosis, though the risk appears relatively low with short-term use. Glucocorticoids, as administered for subacute thyroiditis, have modest benefit in type 2 AIT. Lithium blocks thyroid hormone release and can also provide some benefit. Near-total thyroidectomy rapidly decreases thyroid hormone levels and may be the most effective long-term solution if the patient can undergo the procedure safely.





SOURCE: HARRISON INTERNAL MEDICINE 18 TH ED

AIIMS MAY 14

FORENSIC  QUESTIONS:

1) Section for punishment of perjury is-IPC? ( aiims may 14)
a) 191
b) 193
c) 197
d) 190

2) Criminal responsibility in an alcoholic person is under which IPC?
a) 84 IPC
b) 85
c) 86
d) 83

3) Not a derivative of cannabis?
a) charas
b) hashish
c) afeem
d) THC 

4) Burnt rope smell found in?
a) smoking
b) cannabis
c) alcohol
d) seminal

5)  Eonism is-
a) pleasure by fondling female parts
b) pleasure by wearing female dress
c) pleasure by showing private [parts
d) pleasure by urination

6) Viper bite is- 
 a) vasculotoxic
b) neurotoxic
c) myotoxic
d) nontoxic 

7) Active principle of white oleander?
a) nerin
b) recin
c) oleandrin
d) abrin

8)  Most reliable criteria in gustafson methods? ( aiims may 14)
a) root resorption
b) root transparency
c) cementum
d) root absorption

9) All about is brain death is true except?( aiims may 14)
a) positive apnoea test
b) complete cessation of heart beat
c) complete cessation of all reflexes in all the limb
d) absence of painful stimuli   
  

DIABETIC RETINOPATHY

DIABETIC RETINOPATHY:

 Exudate in the right macular area.

                           
                             cotton wool spot.

 NVD.

 Red flame and Blot haemorrhage.

























Modifiable risk factors:
1) Blood  Glucose
2) Blood Presssure
3) Smoking
4) Lipid level
Non modifiable Risk Factors:
1) Duration
2) age
3) genetic predisposition
4) ethnicity


Pathophysiologic events in  diabetic retinopathy:

1) Basement membrane thickening
2) Pericyte loss
3) Increased capillary  permeability
4) Microaneurysms
5) capillary weaking
6) Rettinal blood flow
7) smooth muscle death


Investigative techniques to assess diabetic  retinopathy

Retinal photography
Fundus f uorescein angiography
Optical coherence tomography
Ultrasound B scan examination
perimetry

LESIONS:

Microaneurysms and retinal hemorrhages
The lesions that the Early Treatment Diabetic Retinopathy Study (ETDRS)  described as critical to the stages of progression of DR were:
• Microaneurysms – a microaneurysm is defined as a red spot < 125 μ m (approximate width of vein at disc margin) and sharp margins.
• Small retinal hemorrhages – a hemorrhage is defined as a red spot, which has irregular margins and/or uneven density, particularly when surrounding a smaller central lesion considered to be a microaneurysm.
Hemorrhage/microaneurysm (HMa) – because the ETDRS recognized that it was very difficult to differentiate between microaneurysms and small hemorrhages, the concept of HMa was introduced, which is a small hemorrhage or microaneurysm .


Other larger  retinal hemorrhages:
• Flame hemorrhages – superficial hemorrhages just under the nerve fiber layer.

Blot hemorrhages – deeper hemorrhages, which are a sign of retinal ischemia in the area of the retina in which they occur.

Hard exudates: Hard exudates (sometimes now just referred to as exudates) are defined as small white or yellowish - white deposits with sharp margins, located typically in the outer layers of the retina, but
they may be more superficial, particularly when retinal edema is present .
Cotton wool spots : Cotton wool spots (referred to as soft exudates in the ETDRS, but this term is now rarely used) are fluffy white opaque areas caused by an accumulation of axoplasm in the nerve fiber layer of the retina, which is caused by an arteriolar occlusion in that area of retina that is apparent on a fl uorescein angiogram.

Intraretinal microvascular abnormalities
IRMA are defined as tortuous intraretinal vascular segments, varying in caliber, derived from remodeling of the retinal capillaries and small collateral vessels in areas of microvascular occlusion and are therefore a sign of retinal ischemia
Venous abnormalities:
• Venous loops – abrupt curving deviations of a vein from its normal path
• Venous beading – in the ETDRS, venous beading is described as a localized increase in caliber of the vein and the severity is dependent on the increase in caliber and the length of vein involved. It is associated with retinal ischemia .
Other venous changes that occur in DR are as follow:
• Venous dilatation;
• Venous narrowing;
• Opacification of the venous wall
• Perivenous exudate

Arteriolar abnormalities
Other arteriolar changes that occur in DR are as follow:
• Arteriolar narrowing;
• Opacification of arteriolar walls
• Arteriovenous nipping.
Fibrous proliferation at the disc
Fibrous proliferation at the disc (FPD) usually occurs when new vessels at the disc start to regress and fi brosis occurs.
Fibrous proliferation elsewhere
Fibrous proliferation elsewhere (FPE) usually occurs when new vessels elsewhere start to regress and fi brosis occurs.

New  vessels on and/or within 1 disc diameter of the disc For new vessels on and/or within 1 disc diameter (DD) of the disc (NVD),

New vessels elsewhere
For new vessels elsewhere (NVE),

Vitreous hemorrhage
Vitreous hemorrhage (VH) is a hemorrhage that is in the vitreous gel.

Preretinal hemorrhage
Preretinal hemorrhages (PRH) are boat - shaped hemorrhages and roughly round, confl uent or linear patches of hemorrhage just anterior to the retina or under the internal limiting membrane.
Post laser treatment:
Photocoagulation laser scars may be seen both after macular or
panretinal laser treatment

Maculopathy
Clinical classification of diabetic maculopathy
Pathophysiology o f macular edema:

In focal macular edema, focal leakage tends to occur from microaneurysms, often with extravascular lipoprotein in a circinate pattern around the focal leakage In diffuse macular edema, there is a generalized breakdown of the blood – retina barrier and profuse early leakage from the entire capillary bed of the posterior pole . causing extracellular fluid accumulation, often accompanied by cystoid macular edema, which is caused by cellular swelling. In ischemic maculopathy, enlargement of the foveal avascular zone as a result of capillary closure is found inducdiabetic maculopathy edema by 50% or more. It also described
“ clinically signifi cant macular edema, ” which defi ned the parameters for treatment as :
• Thickening of the retina at or within 500 μ m of the center of the macula;
• Hard exudates at or within 500 μ m of the center of the fovea, if associated with thickening of the adjacent retina (not residual hard exudates remaining after disappearance of retinal thickening);
• A zone or zones of retinal thickening 1 disc area or larger, any part of which is within 1 DD of the center of the macula



Mild non - proliferative diabetic retinopathy and background diabetic retinopathy :
The earliest sign of mild non - proliferative DR (mild NPDR) or background DR is microaneurysms.
Microaneurysms
Patients with no DR and microaneurysms only were not included in the ETDRS study. In the Wisconsin Epidemiological Study of Diabetic Retinopathy, the rate of progression to proliferative retinopathy 4 years after the initial evaluation showed “ no DR ” was 0.4% for young patients < 30 years with T1DM, 0% for older patients ≥ 30 years with diabetes taking insulin and 0.6% for those not using insulin. For those with microaneurysms or one hemorrhage in one eye only, the rate of progression to proliferative retinopathy 4 years after the initial evaluation was 3.0% for young patients < 30 years with T1DM, 0% for older patients ≥ 30 years with T1DM and 1.5% for those not using insulin. The other signs of mild NPDR are one or more of the following:
• Retinal hemorrhages . In mild NPDR, retinal hemorrhages are
usually small dot hemorrhages or fl ame - shaped hemorrhages
(Figures 36.9 and 36.10 ). Because small retinal hemorrhages can
be diffi cult to differentiate from microaneurysms they are commonly
referred to as HMa.
• Exudates (or hard exudates) are a feature of mild NPDR
• Cotton wool spots may be present in mild NPDR or background DR but are caused by an arteriolar occlusion in that area of retina, but despite this being the underlying cause, they are not a good
sign of increasing retinal ischemia. They are often associated with hypertension
• A single venous loop. The ETDRS included a single venous loop in their classifi cation of mild NPDR; however, this rarely occurs in isolation without other signifi cant signs of retinal ischemia and a venous loop is therefore not a feature of the English Screening defi nition of background DR .
For mild NPDR, there is a 6.2% risk of progression to proliferative retinopathy within 1 year.
The International classification of DR recommends that anyone who has a more severe disorder than microaneurysms is referred to an ophthalmologist . In the UK, patients who are screened and who show signs of background DR are only rescreened annually. For the purposes of the English National
Screening Programme, background DR is defined by the following
lesions
• Microaneurysm(s); and
• Retinal hemorrhage(s) with or without any exudate

Moderate and severe non - proliferative
diabetic r etinopathy:
The main features that warrant classifying a DR level in the higher levels of moderate and severe NPDR  (or pre - proliferative DR  are increasing signs of retinal ischemia.
Lesions associated with increasing retinal ischemia:
• Retinal hemorrhages especially blot hemorrhages
• Intraretinal microvascular abnormality
Intraretinal microvascular abnormalities are derived from remodeling of the retinal capillaries and small collateral vessels in areas of microvascular occlusion. They are usually found on the borders of areas of non - perfused retina.
• Venous beading  is found to be associated with retinal ischemia and is used for assessment of severity
of DR. With increasing ischemia, there is an increasing risk of progression to proliferative in 1 year. The risk increases from approximately 11.3% in the lower levels of moderate NPDR to 54.8% progression to proliferative in 1 year in the most severe NPDR level. ETDRS defi nitions have been simplifi ed to make them easier for everyday clinical use both in the International classifi cation and in the English classifi cation for screening. The ETDRS “ 4 : 2 : 1 rule ” indicates that the presence of severe hemorrhages in four quadrants ( ≥ 20), VB in two quadrants or IRMA in a single quadrant represents this severity of retinopathy,severe NPDR. In the International classifi cation, severe NPDR is defi ned by any of the following:
• Extensive intraretinal hemorrhages ( > 20) in four quadrants;
• Definite VB in two or more quadrants;
• Prominent IRMA in one or more quadrant, and no signs of PDR. Moderate NPDR is classifi ed in the International classifi cation as more than “ microaneurysms only ” and less severe than the
4 : 2 : 1 rule.In the English Screening classifi cation, pre - proliferative DR is defined by any of the following:
• VB
• Venous loop or reduplication;
• IRMA; or
• Multiple deep, round or blot hemorrhages.


Proliferative d iabetic r etinopathy and
a dvanced d iabetic r etinopathy

New vessels arise from the post capillary venule in areas of ischemic retina. New vessel growth originates either within 1 DD of the optic disc (new vessels at the disc [NVD]) or developing
from retinal vessels more than 1 DD away from the edge of the optic disc (new vessels elsewhere [NVE]).


Diabetic Retinopathy Study
The Diabetic Retinopathy Study (DRS)  recommended prompt treatment in the presence of DRS high - risk characteristics, which reduced the 2 - year risk of severe visual loss by 50% or
more and were defined by:
• Presence of preretinal or vitreous hemorrhage;
• Eyes with NVD equalling or exceeding one - quarter to one - third disc area in extent with no hemorrhage;
• NVE equalling more than half disc area with hemorrhage.

Untreated, eyes with high risk characteristics had a 25.6 – 36.9% chance of severe visual loss within 2 years, depending on the size and location of the new vessels and whether or not hemorrhage was present.

“ Low risk ” proliferative patients
In eyes with PDR without high risk characteristics, there were still the following risks of severe visual loss:
• Untreated: 2 year 7.0%, 4 years 20.9%;
• Treated: 2 year 3.2%, 4 years 7.4%.

These risks need to be balanced against the potential adverse effects of laser treatment.
Adverse effects of laser treatment:

• Loss of peripheral areas of visual fi eld was attributed to argon laser in approximately 10% of eyes and fi eld loss was nearly three times more common in the xenon arc treated group.
• Visual acuity loss at the 6 - week follow - up visit was assumed to be brought about by treatment. Among eyes with NPDR, 14.3% more argon - treated and 29.7% of xenon - treated eyes than control subjects had an early persistent loss of one or more lines.
Other possible adverse effects of panretinal laser treatment are as follow:
• Unintended laser absorption (e.g. to the lens) or uptake of laser from a fl ame - shaped hemorrhage, which may result in a burn and destruction of the nerve fiber layer that lies on its surface.
• Inadvertent coagulation (e.g. to the fovea).
• Choroidal detachment is usually as a result of a large dose of laser treatment being applied in a single session, which usually resolves spontaneously within 10 days.

Factors other than h igh risk c haracteristics influencing the decision to laser
Anterior s egment n eovascularization
Extensive neovascularization in the anterior chamber angle is an urgent indication for scatter laser photocoagulation, if it is feasible Signs of ischemia
Large IRMA, VB in more than one quadrant, extensive retinal hemorrhages and opaque small arteriolar branches are signs suggesting
severe retinal ischemia
Macular edema





Pregnancy and the diabetic eye
Risk factors for progression of d iabetic retinopathy in pregnancy
The known risk factors for progression of DR in pregnancy
are:
 Pregnancy itself is independently associated with progression of DR
• Baseline severity of DR
• Poor metabolic control at conception [91] ;
• Rapid improvement of glycemic control [90– 93];
• Poor metabolic control during pregnancy or the early postpartum period
• Duration of diabetes
• Chronic hypertension and pregnancy- induced hypertension





source: text book of Diabetes, Pickup,jossling and Harrison internal medicine.

A 52-year-old man presents to your clinic with a few months history of intermittent paresthesias (tingling and numbness) and mild pain in the bottom of his feet. Examination shows normal mental status, brisk reflexes at the knees, but absent ankle jerks, upgoing toes and hypoesthesia to pinprick in the bottom of his feet. Vibration sensation is decreased in the toes.

You order blood work to evaluate for possible causes of peripheral neuropathy or polyneuropathy. Which abnormal finding is most likely?

a) Low TSH
b) High TSH
c) Low B12
d) High B6
e) High Glucose


ans: This patient has features suggesting a peripheral neuropathy (paresthesias or tingling and pain in the feet) PLUS a myelopathy (upgoing toes and brisk knee jerks), raising the possibility of subacute combined degeneration, a complication of severe vitamin B₁₂ deficiency. Thyroid disease (hypo or hyperthyroidism), B₆ intoxication, and hyperglycemia can all cause peripheral neuropathies but are unlikely to produce signs of a myelopathy, such as those described above. Other causes of subacute combined degeneration include neurosyphilis, tropical myeloneuropathies, Lyme disease, multiple sclerosis, HIV-1 associated vacuolar myelopathy, etc.

49-year-old, previously healthy woman presents to the emergency department because of difficulty walking and bilateral foot pain. This was preceded 2 weeks earlier by a gastrointestinal syndrome with 2 days of diarrhea. She states that she developed some weakness in her feet 4 days ago, but today she has barely been able to walk. She has also noticed decreased handgrip strength and mild dyspnea. In addition, she describes burning pain in her feet and lancinating lower back pain. She has no bowel or bladder symptoms. Your exam shows BP 198/105, pulse 110, respiratory rate 28/minute. O₂ sat is 98% on room air. Her lungs are clear. She has a normal mental status, cranial nerve examination, and finger nose finger testing. She has no reflexes in any limb. Arm strength is good except for hand intrinsic muscles that are 4-/5. Leg muscle strength includes 3/5 weakness of foot dorsiflexion and plantar flexion and 4/5 hip flexion and knee extension. The sensory exam shows some decreased vibration sense and some pinprick hyperalgesia in the soles of her feet. She has difficulty walking and a bilateral steppage gait.

Which of the following tests would you do next?

• a) MRI of the lumbosacral spine
• b) Lumbar puncture
• c) Anti-Hu antibodies
• d) Lyme serology
• e) Vitamin B₁₂ levels

ans:The presentation with a painful, symmetric, ascending (motor more than sensory) polyneuropathy, with no reflexes, is consistent with an acute inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome (GBS). Lumbar puncture is important to rule out infectious and inflammatory causes of a polyradiculopathy. It may also show a “cytoalbuminolgic dissociation” (high protein, with no or few white blood cells; WBCs), characteristic of GBS – after the first week or so. MRI of the lumbosacral spine is worthwhile if an acute lumbosacral polyradiculopathy (cauda equina syndrome) is the initial diagnosis, but upper extremity involvement and respiratory problems make this unlikely. Anti-Hu antibodies are associated with paraneoplastic polyneuropathies (sensory ganglionopathy or sensorimotor polyneuropathy) that are unlikely to present acutely as in this case. Lyme serology is always worthwhile, but nothing in this case points to a history of a tick bite or other typical finding in that disease. B₁₂ deficiency would not explain this clinical picture.
This patient has signs of respiratory distress, with a RR of 28/minute and symptoms of dyspnea. Weakness may be progressing to involve respiratory muscles (particularly the diaphragm), and respiratory failure could occur at any time, requiring intubation. When the FVC is less than 15 mL/kg and the NIF closer to zero (normal is at least −60 cm H₂O) or less (negative) than −25 cm H₂O, prophylactic intubation and ventilation should be considered. Also, a decrease of more than 30% of FVC or NIF in 24 hours may indicate the need for intubation. Nerve conduction studies and EMG can help in the diagnostic evaluation of GBS but are not a task to be done in the emergency department. Additionally, this patient is already presenting signs of autonomic instability (with hypertension and tachycardia) that could change to hypotension or bradycardia at any time. ICU admission is required.
he use of IVIG or plasmapheresis is the first line of therapy in patients with GBS with progressive weakness. IV steroids and oral prednisone are not beneficial and could be potentially harmful. Intubation is not indicated as the FVC and NIF remain stable. Observation alone is not appropriate in patients with significant weakness and respiratory or autonomic compromise.