Thyroxine replacement in ischaemic heart disease

Hypothyroidism and ischaemic heart disease are both common, so inevitably they will sometimes occur together. Although angina may remain unchanged in severity or paradoxically disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and sudden death are well-recognised complications of thyroxine replacement, even using doses as low as 25 μg per day. In patients with known ischaemic heart disease, thyroxine should be introduced at low dose and increased very slowly under specialist supervision. It has been suggested that T3 has an advantage over T4, since T3 has a shorter half-life and any adverse effect will reverse more quickly, but the more distinct peak in hormone levels after each dose of T3 is a disadvantage. Approximately 40% of patients with angina cannot tolerate full replacement therapy despite the use of β-blockers and vasodilators; coronary artery surgery or balloon angioplasty can be performed safely in such patients and, if successful, allow full replacement dosage of thyroxine in the majority

HYPOTHYROIDISM

Thyroid Hormone Physiology:

● Thyroid hormones are necessary for the normal metabolism of human body
● They have an important role to play in acceleration of growth and development
● They have a role in increasing body’s calorie production as per requirement
● Every tissue of body is affected directly or indirectly by the actions of the hormones
● The functions of thyroid hormones include:
● regulation of basal metabolic rate and adjustments of resting oxygen
consumption
● increased uptake, synthesis and utilization of glucose and heat production
● sympathomimetic effects including increased heart rate and force of contraction

Thyroid Hormone Control:

● Hypothalamic-pituitary-thyroid axis controls synthesis and release of thyroid hormones
● The hypothalamus synthesizes a peptide thyrotropin releasing hormone (TRH)
● TRH stimulates pituitary thyrotrophs to produce thyroid stimulating hormone (TSH)
● TSH travels to and stimulates the thyroid gland, trophically to produce T4 and T3
T4 - T3 conversion:
● The major product of thyroid gland is T4. It accounts for 85% of thyroid hormone output
● T4 is metabolized by mono-deiodination to T3 , the more potent, biologically active form
● Circulating T4 has a half-life of seven days, whereas T3 has a half life of only one day

Thyroid Hormone Receptors:

● 3 receptors mediate the primary actions of thyroid hormone
● These are named as TRa1, TRß1, and TRß2
● Interaction of T3 with its receptor promotes binding of cofactors
● These cofactors regulate expression of thyroid-hormone-responsive genes
● They act either through activation or repression of transcription

Hypothyroidism:

● Definition: It is the manifestation of effects of reduced thyroid hormones in human
tissues
● 1.8% of total population affected and 2nd only to DM as commonest endocrine disorder
● Incidence increases with age and it is more common in females - 2-3% of older women
Classification of Hypothyroidism:
● Clinical Hypothyroidism (Overt Hypothyroidism)
● Symptoms are manifest - TSH is high and serumT3 and T4 are low
● Subclinical Hypothyroidism (Mild Hypothyroidism)
● No symptoms - Mild TSH
and Normal T3 & T4
● Euthyroid individual –
● Normal thyroid function Normal TSH – Normal T4 and T3

Etiology:

● PRIMARY HYPOTHYROIDISM - 99%
● Hoshimoto’s thyroiditis is the most common cause
● Idiopathic hypothyroidism is also probably cases of old Hoshimoto’s Thyroiditis
● Irradiation or Surgical removal of thyroid or Drug therapy
● Iodine deficiency is still the most common cause of hypothyroidism
● Infiltrative Diseases: Sarcoidosis, Amyloidosis
● SECONDARY HYPOTHYROIDISM [1%]
● Decreased TSH production and resultant reduction in T4
● Pituitary neoplasm, Pituitary necrosis (Sheehan’s syndrome)
● Congenital hypopituitarism
● Hypothalmic dysfunction (Teritiary Hypothyroidism)

Hashimoto’s Thyroiditis:

● Dr. Hakaro Hashimoto was born in Iga-Ueno in Japan in the year 1881
● He graduated in Medicine form Kyushu Imperial Medical University
● In 1912, he described the chronic thyroid disorder
● He termed it as Struma Lymphamatosa; but now called as Chronic Lymphocytic
Thyroiditis
● It is characterized by diffuse lymphocytic infiltration, fibrosis and parenchymal atrophy
Pathogenesis:
● Reduced metabolic rate causes reduced performance
● Hence weight gain occurs despite a poor appetite
● The pathology is deposition of Glycos-Amino Glycans(GAG) in tissues
● GAG is hygroscopic and causes mucinous edema
● Hence this results in a boggy non-pitting edema in tissues which are lax
● Skin and hair effects:
● Skin has reduced sweating and sebaceous secretions
● And there is thinning of epidermis, hyperkeratosis of stratum corneum
● Hence the skin is pale, cool, dry and coarse
● Capillary
fragility causes easy bruisability
● Scalp and body hair as well as the nails are dry and brittle
● Cardiovascular effects:
● Decrease in heart rate, pulse pressure and ¯ in the cardiac output
● ¯ blood supply and vasoconstriction of skin – results in cold intolerance
● Increased systemic vascular resistance – leads to increase in DBP
● Flabby myocardium and pericardial effusions are common
● ECG changes – sinus bradycardia, low voltage, ST & T changes
● Respiratory and GIT effects:
● Hoarseness of voice – due to GAG deposition in larynx
● Obstructive sleep apnoea to a thick tongue falling back
● Constipation due to reduced gut peristalsis
● Myxedema megacolon and Myxedema ileus are uncommon
● Neuromuscular effects:
● Slowed physical and mental functions leads to lethargy and increased somnolence
● Carpel tunnel syndrome due to deposition of GAG
● Delayed relaxation of ankle jerk is a useful bed side clinical finding
● Deafness and depression and rarely Myxedema madness may occur
Signs and Symptoms:
● These are non-specific and gradual in onset
● May be confused with other conditions like postpartum depression and Alzheimer’s
● One must maintain high index of suspicion
Common signs and symptoms:
Laboratory values

Additional Tests:

● Once diagnosis of primary hypothyroidism is made,
● Additional imaging or serologic testing are unnecessary if gland is WNL
● In secondary cases, further testing with pituitary provocative testing
● imaging with CT scan annd or MRI to rule out microadenoma
● Evidence of ¯ of >1pituitary hormone indicates a panhypopituitary problem
● Serum cholesterol may be elevated. Complete lipid profile and ECG studies
● Prolactin levels are elevated in Secondary Hypopiuitarism
● Blood Haemoglobin and ferritin testing for anaemia are indicated in most cases
Antibodies in hypothyroidism:
● Anti Thyroid Per-Oxidase [anti microsomal] antibodies – Anti-TPO in most cases
● Anti thyroglobulin antibodies – Anti TG. Also found elevated in Hashimoto’s Thyroiditis
● Anti bodies against T3 and T4 in auto immune disease.
● Anti TSH Receptor and Anti-T3 T4 Receptor antibodies are also sometimes seen
● Anti gastric parietal cell antibodies are seen in 10% and this may lead to Pernicious
Anemia

Thyroid Hormone Replacement:

● Most healthy adults require 1.7 ugm/kg/day – 100-150ug/day
● Levothyroxine cause increases in resting heart rate and BP
● Start at low doses in older and if cardiovascular compromise
● Elderly, dosage falls down to – 1.0 ugm/kg/day -50-100ug/day
● For full replacement children need up to 4ugm /kg/day

Monitoring thyroid function:

● Followed by serial TSH measurements
● Changes in TSH levels lag behind serum T3 T4
● Resetting pituitary gland takes about 1 month
● So TSH not be checked sooner than 4 weeks
● Goal to keep TSH in lower half of normal range
● No need to monitor the T3 T4 levels normally
● In pituitary insufficiency T3 & T4 are followed
● Goal to keep T3 T4 in upper range of normal
● Once stable TSH or Free T4 monitored yearly
● Once stable it remains stable until 60-70 yrs

Pregnancy and Thyroid:

● During pregnancy the requirement for FT4 increases by 25-50%
● Estrogens
® TBG
® ¯FT4 ® TSH
+ TPO

Ab ®Hypothyroidism

● Miscarriage, preterm delivery, preeclampsia & placental abruption
● Can lead to ¯intellectual capacity & developmental delay in children
● (AACE) recommend universal thyroid testing for pregnant women
Myxedema coma:
● High mortality rate, despite intensive treatment
● Myxedema coma almost always occurs in the elderly
● Reduced consciousness, seizures + other features of hypothyroidism
● Precipitated by factors that impair respiration like sedatives
● Other precipitating factors - MI, CCF, CVA, UGIB and Pneumonia
● Myxedema coma-Treatment:
● Levothyroxine A single IV bolus of 500 g loading dose
● Levothyroxine is continued at a dose of 50 to 100 g/day
● If IV is not available the same initial dose by NG tube
● Supportive therapy:
● Correct metabolic disturbances & precipitating factors
● Hydrocortisone 50mg q6h should be administered
● Early use of broad-spectrum antibiotics for infection
● Space blankets should be used to prevent heat loss
● External warming for <300C, otherwise CV collapse
● Hypertonic saline if there is hyponatremia
● Hypotonic IV fluids avoided because water retention
● Intravenous glucose if there is hypoglycemia
● Sedatives avoided and blood levels monitored
● Ventilator support with regular blood gas analysis

Subclinical Hypothyroidism

● Definition: Biochemical evidence but no clinical evidence
● No universal consensus in treatment of mildly elevated TSH
● Little risk if excessive treatment is avoided and clinical benefits
● Patients will progress to overt HYPO if TSH is >6mU/l
● Start with low dose 25-50 ug/day and slowly titrate upwards

Risk of over treatment

● Over treatment may result in atrial fibrillation
● Otherwise there is a risk of development of osteoporosis
● Then there is a possibility of inducing frank hyperthyroidism
● Emotional lability, nervousness, irritability, poor concentration
● Start with low dose 25-50 ug/day and slowly titrate upwards

HEPATITIS B

The hepatitis B virus consists of a core containing DNA and a DNA polymerase enzyme needed for virus replication. The core of the virus is surrounded by surface protein . The virus, also called a Dane particle, and an excess of its surface protein (known as hepatitis B surface antigen) circulate in the blood. Humans are the only source of infection. . Hepatitis B surface antigen (HBsAg) is a protein which makes up part of the viral envelope. Hepatitis B core antigen (HBcAg) is a protein which makes up the capsid or core part of the virus (found in the liver but not in blood). Hepatitis B e antigen (HBeAg) is part of the HBcAg which can be found in the blood and indicates infectivity. Hepatitis B infection affects 300 million people and is one of the most common causes of chronic liver disease and hepatocellular carcinoma world-wide. Hepatitis B may cause an acute viral hepatitis; however, the acute infection is often asymptomatic, particularly when acquired at birth. Many individuals with chronic hepatitis B are also asymptomatic. Chronic hepatitis, associated with elevated serum transaminases, may occur and can lead to cirrhosis, usually after decades of infection  The risk of progression to chronic liver disease depends on the source of infection  Vertical transmission, from mother to child in the perinatal period, is the most common cause of infection world-wide and carries the highest risk.  SOURCE OF HEPATITIS B INFECTION AND RISK OF CHRONIC INFECTION Route of transmission Risk of chronic infection Horizontal transmission 10% Injection drug use   Infected unscreened blood products   Tattoos/acupuncture needles   Sexual (homosexual and heterosexual)   Vertical transmission 90% HbsAg-positive mother   There is an initial immunotolerant phase with high levels of virus and normal liver biochemistry. An immunological response to the virus then occurs, with elevation in serum transaminases which causes liver damage: chronic hepatitis. If this response is sustained over many years and viral clearance does not occur promptly, chronic hepatitis may result in cirrhosis. In individuals where the immunological response is successful, viral load falls, HBe antibody develops and there is no further liver damage. Some individuals may subsequently develop HBV-DNA mutants, which escape from immune regulation, and viral load again rises with further chronic hepatitis. Mutations in the core protein result in the virus's inability to secrete HBe antigen despite high levels of viral replication; such individuals have HBeAg-negative chronic hepatitis. (ALT = alanine aminotransferase; AST = aspartate aminotransferase)  (HBsAg = hepatitis B surface antigen; anti-HBs = antibody to HBsAg; HBeAg = hepatitis B e antigen; anti-HBe = antibody to HBeAg; anti-HBc = antibody to hepatitis B core antigen)  INTERPRETATION OF MAIN INVESTIGATIONS USED IN THE SEROLOGICAL DIAGNOSIS OF HEPATITIS B VIRUS INFECTION     Anti-HBc   Interpretation HBsAg IgM IgG Anti-HBs Incubation period + + - - Acute hepatitis Early + + - - Established + + + - Established (occasional) - + + - Convalescence   (3-6 months) - ± + ±   (6-9 months) - - + + Post-infection > 1 year - - + + Uncertain - - + - Chronic infection Usual + - + - Occasional - - + - Immunisation without infection - - - + + positive; - negative; ± present at low titre or absent. Investigations Serology HBV contains several antigens to which infected persons can make immune responses  these antigens and their antibodies are important in identifying HBV infection  In acute infection the hepatitis B surface antigen (HBsAg) is a reliable marker of HBV infection, and a negative test for HBsAg makes HBV infection very unlikely but not impossible . HBsAg appears in the blood late in the incubation period and before the prodromal phase of acute type B hepatitis; it may be present for only a few days, disappearing even before jaundice has developed, but usually lasts for 3-4 weeks and can persist for up to 5 months. Antibody to HBsAg (anti-HBs) usually appears after about 3-6 months and persists for many years or perhaps permanently. Anti-HBs implies either a previous infection, in which case anti-HBc (see below) is usually also present, or previous vaccination when anti-HBc is not present. The hepatitis B core antigen (HBcAg) is not found in the blood, but antibody to it (anti-HBc) appears early in the illness and rapidly reaches a high titre which then subsides gradually but persists. Anti-HBc is initially of IgM type with IgG antibody appearing later. Anti-HBc (IgM) can sometimes reveal an acute HBV infection when the HBsAg has disappeared and before anti-HBs has developed (and  The hepatitis B e antigen (HBeAg) appears only transiently at the outset of the illness and is followed by the production of antibody (anti-HBe). The HBeAg reflects active replication of the virus in the liver. The persistence of HBsAg for longer than 6 months indicates chronic infection. Chronic HBV infection (see below) is marked by the presence of HBsAg and anti-HBc (IgG) in the blood. Usually, HBeAg or anti-HBe is also present; HBeAg indicates continued active replication of the virus in the liver while anti-HBe implies that replication is occurring at a much lower level or that HBV-DNA has become integrated into host hepatocyte DNA. Viral load  HBV-DNA encodes four proteins: a DNA polymerase needed for viral replication (P), a surface protein (S), a core protein (C) and an X protein. The pre-C and C regions encode a core protein and an e antigen. Although mutations in the hepatitis B virus are frequent occurrences, certain mutations have important clinical effects. Pre-C encodes a signal sequence needed for the C protein to be secreted from the liver cell into serum as e antigen. A mutation in the pre-core region leads to a failure of secretion of e antigen into serum and so individuals have high levels of viral production but no detectable e antigen in the serum. Mutations can also occur in the surface protein and may lead to the failure of vaccination (surface antibodies produced against native S protein) to prevent infection. Mutations also occur in the DNA polymerase during antiviral treatment with lamivudine. HBV-DNA can be measured by polymerase chain reaction (PCR) in the blood. Viral loads are usually in excess of 105 copies/ml in the presence of active viral replication, as indicated by the presence of e antigen. In contrast, in those with low viral replication, HBsAg- and anti-HBe-positive, viral loads are less than 105 copies/ml. The exception is in patients who have a mutation in the pre-core protein, which means they cannot secrete e antigen into serum . Such individuals will be anti-HBe-positive but have a high viral load and often evidence of chronic hepatitis. These mutations are common in the Far East and those affected are classified as having e antigen-negative chronic hepatitis. They respond differently to antiviral drugs from those with classical e antigen-positive chronic hepatitis. Measurement of viral load is important in monitoring antiviral therapy and identifying patients with pre-core mutants. Specific HBV genotypes can also be identified using PCR. Genotypes B and C appear to have more aggressive disease that responds less well to antiviral therapy. Management Acute hepatitis B Treatment is supportive with monitoring for acute liver failure, which occurs in less than 1% of cases. Chronic hepatitis B Treatments are still limited, with no drug able to eradicate hepatitis B infection completely. The indication for treatment is a high viral load in the presence of active hepatitis, as demonstrated by elevated serum transaminases and/or histological evidence of inflammation. Alfa-interferon This is most effective in selected patients with a low viral load and serum transaminases greater than twice the upper limit of normal in whom it acts by augmenting a native immune response. In HBeAg-positive chronic hepatitis 33% lose e antigen after 4-6 months of treatment compared to 12% of controls. Response rates are lower in HBeAg-negative chronic hepatitis, even when patients are given longer courses of treatment. Interferon is contraindicated in the presence of cirrhosis as it may cause a flare in serum transaminases and precipitate liver failure. Longer-acting pegylated interferons which can be given once weekly have been evaluated in both HBeAg-positive and HBeAg-negative chronic hepatitis . Other antiviral therapies are required because many patients with chronic hepatitis B have high levels of viraemia and/or low transaminase levels and are not therefore candidates for interferon. Lamivudine PEGYLATED INTERFERONS IN CHRONIC HEPATITIS B INFECTION 'In HBeAg-positive chronic hepatitis treatment with pegylated interferon for 6 months eliminates HBeAg in 35%, and normalises liver biochemistry in 25% of patients. In HBeAg-negative chronic hepatitis treatment with pegylated interferon for 12 months leads to normal liver biochemistry in 60%, and sustained suppression of hepatitis B virus load below 400 copies/ml in 20% of patients.'

LAMIVUDINE IN CHRONIC HEPATITIS B INFECTION

'48 weeks of treatment with lamivudine induces anti-HBe seroconversion in 27% of patients with HBeAg-positive chronic hepatitis, despite 38% developing HBV-DNA polymerase mutations. Treatment also improves histology and liver biochemistry.'

ADEFOVIR IN CHRONIC HEPATITIS B INFECTION

'In HBeAg-positive chronic hepatitis treatment with 10 mg of adefovir for 48 weeks produces normal liver biochemistry in 48% (NNTB 3), suppresses serum HBV-DNA in 39% (NNTB 5) and leads to e antigen seroconversion in 14% (NNTB 16) of patients. In HBeAg-negative chronic hepatitis treatment with adefovir for 48 weeks reduces ALT to normal in 72% (NNTB 2.3) and renders serum HBV-DNA undetectable in 55% (NNTB 2) of patients.'

This is a nucleoside analogue which inhibits DNA polymerase and suppresses HBV-DNA levels. It is effective in improving liver function in patients with decompensated cirrhosis and may prevent the need for transplantation. Long-term therapy is complicated by the development of HBV-DNA polymerase mutants which may occur after 9 months of treatment and is characterised by a rise in viral load during treatment. These viral mutants are less hepatotoxic than native virus so the drug can often be continued (Box 23.40). Flares in transaminases occur when lamivudine is stopped if mutant virus is present, as native virus replaces mutant virus.

Adefovir

This is a nucleotide analogue that is phosphorylated to yield active drug which inhibits HBV-DNA polymerase. It reduces HBV-DNA levels by 3-4 logs, enhances the frequency of HBeAg seroconversion and leads to histological improvement, but is contraindicated in renal failure. The HBV-DNA mutants develop at a lower rate than with lamivudine, 2% being identified after 2 years of treatment (Box 23.41). Relapse occurs on stopping treatment and the optimum length of treatment remains unknown. Adefovir is effective in suppressing most of the lamivudine-induced DNA polymerase mutant viruses.

Other drugs

Other drugs which are currently been studied in chronic hepatitis B include tenofovir, which has anti-HIV efficacy, and L-deoxythymidine. The role of combination antiviral therapy, as used in HIV infection, is still unclear.

Liver transplantation

Historically, liver transplantation was contraindicated in the presence of hepatitis B because infection often recurred in the graft. However, the use of post-liver transplant prophylaxis with lamivudine and hepatitis B immunoglobulins has reduced the reinfection rate to 10% and increased 5-year survival to 80%, making transplantation an acceptable treatment option in selected cases.

Prevention

AT-RISK GROUPS MERITING HEPATITIS B VACCINATION IN LOW ENDEMIC AREAS

Parenteral drug users Men who have sex with Close contacts of infected individuals Newborn of infected mothers Regular sexual partners Patients on chronic haemodialysis Patients with chronic liver disease men Medical/nursing personnel

Individuals are most infectious when markers of continuing viral replication, such as HBeAg, and high levels of HBV-DNA are present in the blood; they are least infectious when only anti-HBe is present with low levels of virus. HBV-DNA can be found in saliva, urine, semen and vaginal secretions. The virus is about ten times more infectious than hepatitis C, which in turn is about ten times more infectious than HIV.

A recombinant hepatitis B vaccine containing HBsAg is available (Engerix) and is capable of producing active immunisation in 95% of normal individuals. The vaccine gives a high degree of protection and should be offered to those at special risk of infection who are not already immune, as evidenced by anti-HBs in the blood . The vaccine is ineffective in those already infected by HBV. Infection can also be prevented or minimised by the intramuscular injection of hyperimmune serum globulin prepared from blood containing anti-HBs. This should be given within 24 hours, or at most a week, of exposure to infected blood in circumstances likely to cause infection (e.g. needlestick injury, contamination of cuts or mucous membranes). Vaccine can be given together with hyperimmune globulin (active-passive immunisation).

Neonates born to hepatitis B-infected mothers should be immunised at birth and given immunoglobulin. Hepatitis B serology should then be checked at 12 months of age.

Prognosis

Acute hepatitis

Full recovery occurs in 90-95% of adults following acute HBV infection. The remaining 5-10% develop a chronic infection which usually continues for life, although later recovery occasionally occurs. Infection passing from mother to child at birth leads to chronic infection in the child in 90% of cases and recovery is rare. Chronic infection is also common in immunodeficient individuals such as those with Down's syndrome or HIV infection.

Recovery from acute HBV infection occurs within 6 months and is characterised by the appearance of antibody to viral antigens. Persistence of HBeAg beyond this time indicates chronic infection. Combined HBV and HDV infection causes more aggressive disease.

Chronic infection

Most patients with chronic hepatitis B are asymptomatic and develop complications such as cirrhosis and hepatocellular carcinoma only after many years . Cirrhosis develops in 15-20% of patients with chronic HBV over 5-20 years. This proportion is higher in those who are e antigen-positive.

HYPERTHYROIDISM

Hyperthyroidism

Disease processes associated with increased thyroid secretion result in a predictable hypermetabolic state. Increased thyroid secretion can be caused by primary alterations within the gland (Graves' disease, toxic nodular goiter, toxic thyroid adenoma) or central nervous system disorders and increased TSH-produced stimulation of the thyroid. Most hyperthyroid states occur because of primary malfunction. Even more unusual hyperthyroid states can result from mismanaged exogenous thyroid ingestion, molar pregnancy with increased release of human chorionic gonadotropin, and unusually, thyroid malignancy with overproduction of thyroid hormone.

Graves' Disease

Grave's disease is the most common cause of hyperthyroidism (diffuse toxic goiter). This disease entity was originally described by an Irish physician, Dr. Robert Graves, in 1835. Women between the ages of 20 and 40 years are most commonly affected. The hyperthyroidism in Grave's disease is caused by stimulatory autoantibodies to TSH-R. Although several theories about the stimulus that initiates production of these antibodies have been proposed, there is no universal agreement about the etiology of the process. Genetic susceptibility to this disease is possible as evidenced by the increased probability of Grave's disease in monozygotic twins.

Pathology

On microscopic examination, the follicles are small with hyperplastic columnar epithelium. Hyperplasia of these cells is exhibited by rapidly dividing nuclei and papillary projections of the follicular epithelium within the central follicles. Increased deposition of lymphoid tissue is also demonstrable in many patients with Graves' disease.

Clinical Features

A patient with classic Graves' disease usually has a visibly enlarged neck mass consistent with a goiter that may demonstrate an audible bruit secondary to increased vascular flow. Clinical thyrotoxicosis and exophthalmos complete the classic triad of the disease. Hair loss, myxedema, gynecomastia, and splenomegaly can accompany the clinical findings. Tracheal compression can result in symptoms of airway obstruction, although acute compression with respiratory distress is exceedingly rare.

The ocular consequences of prolonged and untreated thyrotoxicosis, such as proptosis, supraorbital and infraorbital swelling, and conjunctival swelling and edema, can be severe. The ophthalmopathy is thought to be due to stimulation of the overexpressed TSH-R in the retro-orbital tissues of Grave's patients. In its most severe form, spasm of the upper eyelid resulting in retraction and visualization of a larger amount of sclera than normal can lead to lid lag and exacerbation of the already swollen conjunctiva. All these pressure-related phenomena can progress to decreased oculomuscular movements, ophthalmoplegia, and diplopia. Optic nerve damage and blindness can be a long-term consequence if the underlying condition is not corrected. However, this is rarely seen currently with improved screening assays that detect Grave's disease at early stages. Sustained hyperthyroidism is treated aggressively to remove the stimulus to the retro-orbital tissues.

The hypermetabolic state of hyperthyroidism is clinically manifested as sweating, weight loss, heat intolerance, and thirst. Cardiovascular stress can be demonstrated by high-output cardiac failure, congestive heart failure with peripheral edema, and arrhythmias such as ventricular tachycardia or atrial fibrillation. Gastrointestinal signs may include diarrhea and electrolyte wasting. The menstrual cycle can be altered to the point of amenorrhea. Psychiatric signs may include altered sleep patterns, emotional mood swings, fatigue, excitability, and agitation.

Diagnosis

An enlarged smooth thyroid mass and signs and symptoms of thyrotoxicosis suggest the diagnosis. A cost-effective workup can include an extensive history, physical examination, and thyroid function tests. In addition to elevated levels of T₃ and T₄, a decreased or undetectable level of TSH is demonstrated. Thyroid antibodies are usually detected in elevated quantities. An ¹²³I radionuclide scan demonstrates diffuse uptake throughout an enlarged gland. Ultrasound or computed tomography (CT) of the neck can be used to evaluate clinical landmarks . However, the absolute requirement of CT and ultrasound for preoperative assessment is not universally agreed on.

Treatment

When a diagnosis of Graves' disease has been made, therapy is initiated rapidly to ameliorate symptoms and decrease thyroid hormone synthesis. This is particularly crucial for patients with vision-threatening exophthalmos. The former is accomplished with β-blocker therapy, which is started immediately, and the latter with thionamide, radioactive iodine ablation, or surgery, each of which is equally effective in normalizing serum thyroid hormone levels within 6 weeks. Clearly, patients with Grave's disease need to be educated regarding appropriate choices, the risks associated with each treatment, and the expectation of complete success.

Radionuclide Therapy

Radioiodide ablation with ¹³¹I is the therapy of choice in the United States. It ablates the thyroid within 6 to 18 weeks. Patients with mild, well-tolerated hyperthyroidism can safely proceed to radioactive iodine ablation immediately. However, those who are elderly or severely thyrotoxic may require pretreatment with a thionamide. The overall cure rate with radioactive iodine is 90%. Hypothyroidism will develop in cured individuals, hence the need for careful measurement of thyroid hormone and TSH levels at regular intervals after therapy. Most patients are candidates for radioactive iodine; exceptions include women who are pregnant or lactating or those with a suspicious nodule.

Advantages of ¹³¹I therapy include avoidance of surgery and the associated risks of recurrent laryngeal nerve damage, hypothyroidism, or postsurgical recurrence. It may be that ¹³¹I therapy is more cost-effective in the long run; however, the financial advantage is not as clear if repeated ¹³¹I therapy is needed. Additional disadvantages include exacerbation of cardiac arrhythmias, particularly in elderly patients, possible fetal damage in pregnant women, worsening ophthalmic problems, and rare, but possibly life-threatening thyroid storm.

Antithyroid Medication

PTU and methimazole inhibit the organification of intrathyroid iodine, as well as the coupling of iodotyrosine molecules to form T₃ and T₄. PTU has the additive effect of blocking peripheral conversion of T₄ to T₃. This is important because peripheral access to T₃ and T₄ has multiple hyperdynamic and hypermetabolic effects. Additionally, the peripheral adrenergic effects of thyrotoxicosis can be modulated by the use of β-blocking agents such as propranolol. Corticosteroids in combination with β-blockers can help gain rapid control of the hypermetabolic effects of increased peripheral T₄ and T₃. Patients may choose a trial of antithyroid medication over radioactive iodine therapy. The goal of this therapy is to attain euthyroidism; however, hypothyroidism may result and necessitate thyroid hormone replacement. Antithyroid medication is effective in gaining rapid control of thyrotoxicosis, but the relapse rate after discontinuation of medication may approach 50% 12 to 18 months after cessation. Additionally, patients need to be monitored for side effects of the drugs, which may include granulocytopenia and, in rare instances, aplastic anemia. Other side effects include fever, polyarteritis, and rash.

Thyroid Resection

Surgery is advocated by a minority of thyroid specialists in the United States. It is primarily indicated for patients who have an obstructive goiter, have a fear of radioactivity, are noncompliant, or have had an adverse effect with thionamide drugs. Additional candidates are pregnant patients or those with a suspicious nodule. Advantages of surgical ablation of the thyroid include rapid, effective treatment of thyrotoxicosis without the necessity for medications and their accompanying side effects. The amount of residual tissue is a subject of debate. Complete ablation of thyroid tissue requires total thyroidectomy, which is associated with the highest rates of hypoparathyroidism and recurrent laryngeal nerve damage. Some groups have reported that total thyroidectomy is the most effective way to treat patients with severe Graves' disease because it offers the lowest rate of relapse. It may be that patients, particularly those with ophthalmopathy, are stabilized most successfully by total thyroidectomy. Removal of the entire antigenic focus may be the most likely explanation for this observation. Other subtotal resections include near-total thyroidectomy or subtotal thyroidectomy.

Careful documentation of euthyroid status before surgery in all hyperthyroid patients is mandatory. If the patient is not properly treated preoperatively, thyroid storm can be life threatening. Fortunately, this complication is rarely encountered if appropriately anticipated. Thyroid storm is manifested by severe tachycardia, fever, confusion, vomiting to the point of dehydration, and adrenergic overstimulation to the point of mania and coma after thyroid resection in an uncontrolled hyperthyroid patient. The best way to treat thyroid storm is preoperative anticipation and preparation. Additionally, all patients undergoing general anesthesia are checked for undiagnosed hyperthyroidism, if clinically suspected. Treatment of a patient with overt thyroid storm includes rapid fluid replacement and institution of antithyroid drugs, β-blockers, iodine solutions, and steroids. In life-threatening circumstances, peritoneal dialysis or hemodialysis may be effective in lowering T₄ and T₃ levels.

Toxic Nodular Goiter/Toxic Adenoma

Toxic nodular goiter, also known as Plummer's disease, refers to a nodule contained within an otherwise goitrous thyroid gland that has autonomous function. It usually occurs in the setting of a patient with endemic goiter. Increased thyroid hormone production occurs independent of TSH control. Such patients generally have a milder course and are older than those with Graves' disease. The thyroid in these patients may be diffusely enlarged or associated with retrosternal goiters. Initial symptoms are mild, peripheral thyroid hormone levels are elevated, and TSH levels are suppressed. Antithyroid antibody levels are usually decreased. The diagnosis is generally confirmed after clinical suspicion, and an ¹³¹I radionuclide scan is performed that localizes one or two autonomous areas of function while the rest of the gland is suppressed ( Fig. 36-6 ). Toxic nodular goiter can be treated with thionamides, radioiodine therapy, or surgery; however, the latter two are preferred because these nodules rarely resolve with prolonged thionamide therapy. Radioiodine is widely used for patients with toxic adenomas, although it is not as effective as in Grave's disease. Most patients are euthyroid after radioiodine therapy because the radioiodine preferentially accumulates in hyperfunctioning nodules. The surgical approach is lobectomy or near-total thyroidectomy, particularly when clinical symptoms are pronounced. In the case of a single, hyperfunctioning adenoma, lobectomy is generally curative.

Nontoxic Goiter

Multinodular Goiter

Multinodular goiter describes an enlarged, diffusely heterogeneous thyroid gland. Initial findings may include diffuse enlargement, but asymmetric nodularity of the mass often develops. The cause of this mass is usually iodine deficiency. Initially the mass is euthyroid, but with increasing size, elevations in T₃ and T₄ can occur and gradually progress to clinical hyperthyroidism. Workup and diagnosis involve evaluation of thyroid function tests. Ultrasound and radioisotopic scanning demonstrate heterogeneous thyroid substance. Nodules with poor uptake can appear as lesions suggestive of malignancy. The incidence of carcinoma in multinodular goiter has been reported to be 5% to 10%. Therefore, FNA for diagnosis and resection for suspicious lesions is considered.

Substernal Goiter

A substernal goiter is an unusual manifestation of intrathoracic extension of an enlarged thyroid that generally occurs as a result of multinodular goiter. Most intrathoracic or substernal goiters are labeled secondary because they are enlargements or extensions of multinodular goiters based on the inferior thyroid vasculature. They expand downward into the anterior mediastinum. The extremely rare (∼1%) primary substernal goiter arises as aberrant thyroid tissue within the anterior or posterior mediastinum and is based on the intrathoracic vasculature and not supplied by the inferior thyroid artery.

Special Considerations for Patients With Goiter

Patients with an enlarged thyroid mass (>5 cm) can have a spectrum of symptoms ranging from none to severe dysphagia, choking, and pain. Occasionally, the diagnosis is suggested by the presence of an anterior mediastinal mass on chest radiography. In 10% to 20% of cases, an asymptomatic patient may have no palpable abnormality in the cervical area and a completely intrathoracic lesion.

CT is the preferred imaging study, and all regions from the mandible to the upper part of the abdomen are included in the scan. The lesion itself is scrutinized. Benign goiters have rounded, smooth borders. Thyroid malignancies generally have more ill-defined borders. CT also allows evaluation of regional lymph nodes and metastasis. If the patient has a history of cervical pain and night sweats, a diagnosis of lymphoma is considered. The use of FNA with CT guidance is important to secure a tissue diagnosis. Magnetic resonance imaging (MRI) does not usually add significant information to a well-performed CT scan. For patients with an intrathoracic lesion and a history of coughing, preoperative bronchoscopy can give important information about vocal cord status and possible luminal invasion by a malignancy.

Almost all goiters and other thyroid masses are initially approached surgically through a cervical incision. Goiters are usually mobilized easily, even when they are substernal. The blood supply is generally based on the inferior thyroid artery, which is in its normal position and allows even large substernal masses to be gently mobilized into the neck. Careful attention must be directed to the location of the esophagus, trachea, and recurrent laryngeal nerve. The esophagus can be injured by overaggressive manipulation of the thyroid mass. The recurrent laryngeal nerve is usually displaced posteriorly and inferiorly; however, it can be draped anteriorly over the mass and damaged in that position. Great care must be exercised in mobilization of the mass until the nerve is identified. The cervical incision is extended to a median sternotomy if there is significant bleeding from the anterior mediastinum, if the anatomy and location of the recurrent laryngeal nerve are in doubt, or if the mass cannot be mobilized through the surgical field.

MYXOEDEMA

Myxoedema means severe hypothyroidism in adults and signs and symptoms are accentuated. The facial appearance is typical

There is often supraclavicular puffiness, a malar flush and a yellow tinge to the skin

Myxoedema coma, characterised by altered mental status, hypothermia and a precipitating medical condition, for example cardiac failure or infection, carries a high mortality rate

Treatment

Thyroid replacement: Either a bolus of 500 mg T4 or 10 micro gram T3 either intravenously or orally every 4-6 hours

For hypothermia(<30 degree) body is warmed slowly

Intravenous broad spectrum antibiotics and steroids

Primary or atrophic myxoedema is considered to be an autoimmune disease similar to chronic lymphocytic thyroiditis Hashimotos) but without Goiter formation,and there is delay in diagnosis and hypothyroidism is severe

Ref : Bailey and Love

RETRO-STERNAL GOITRE

Very few retrosternal goitre arise from ectopic thyroid tissue, most arise from lower pole of nodular goitre. If neck is short and pretracheal muscles are strong especially in men the negative intrathoracic pressure tends to draw these nodules into superior mediastinum

Clinical Features

·         Dyspnoea, particularly at night,cough, stridor

·         Dysphagia

·         Engorgement of facial, neck,superficial chest wall veins: occurs in cases of obstruction of superior venacava

·         Recurrent nerve paralysis; the goiter may be also malignant or toxic

Diagnosis

·         Chest and thoracic inlet Radio graphs

·         CT scan, MRI

·         Flow-volume pulmonary function test; to detect degree of obstruction

Treatment

No role for anti-thyroid drugs and radio-iodine,resection is carried out from neck sometimes median sternotomy is needed. Fragmentation during resection must be avoided in case of malignancy. Recurrent laryngeal N injury is common.

                                                                                                                   

   Ref: BAILEY AND LOVE

HEPATITIS D (DELTA VIRUS)

The HEPATITIS D virus (HDV) is an RNA defective virus which has no independent existence,it requires HBV virus for replication and has got same mode of transmission.It can infect those with HBV and can also cause superinfection on chronic carriers for HBV

Infection is self limiting along with HBV. Simultaneous infection with HBV and HCV Leads on to rapid progressive Hepatitis leading on to cirrhosis

Mode of transmission is similar to HBV

Investigations

HDV virus contain a single antigen to which body makes anti-HDV antibody, delta antigen appears in blood transiently, diagnosis depends on anti-HDV. Antibody usually disappears after 2 months

Super infection produce high titres of anti-HDV.

Management

Effective management of hepatitis B effectively prevents hepatitis D