Causes of thyroid hormone excess
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The major causes of thyrotoxicosis include Graves’ disease, solitary toxic adenoma, and toxic multinodular goiter. In thyrotoxicosis, free hormone levels are invariably increased. The reverse is not true in that increased free thyroid hormone levels do not always point to thyrotoxicosis. In illness or resistance to thyroid hormones increased free hormone levels are present while the patients are clinically euthyroid or even sometimes hypothyroid. Subclinical thyrotoxicosis is defined as a state in which free thyroid homones (FT4 & FT3) are within normal limit, but serum TSH level is low. The most common cause of subclinical thyrotoxicosis is exogenous administration of thyroid hormone rather than Graves’ disease. Patients of subclinical thyrotoxicosis either have no symptoms or have mild non specific symptoms.
The various causes of thyrotoxicosis are listed below in table 1
Clinical manifestations of the thyrotoxicosis are similar for various causes of thyrotoxicosis. However certain features provide some clues about specific cause of throtoxicosis. These features include the duration and mode of onset of thyrotoxicosis, size and shape of the thyroid gland, presence or absence of the extra-thyroidal manifestations like Graves’ eye sign, pre-tibial myxoedema, acropachy. Patient presenting with toxic features can be because of thyroiditis or Graves’ disease, but the symptoms are of few weeks duration in former while in later condition, it is for several months, most of the time. The common clinical features of thyrotoxicosis are listed below in table 2.
Thyroid hormone excess with hyperthyroidism Primary Hyperthyroidism Graves’ Disease Toxic Thyroid adenoma Toxic Multinodular Goiter Metastases from Thyroid carcinoma Mutations of TSH receptor, Gsα (Mc Cune Albright Syndrome) Struma Ovarii Iodine ingestion (jod-Basedow phenomenon) Secondary hyperthyroidism TSH secreting pituitary tumours Pituitary Thyroid hormone resistance Thyroid hormone excess without hyperthyroidism Throiditis: subacute, silent Ingestion of thyroid tissue, thyroid hormone Thyroid gland destruction by amiodarone, radiotherapy, infarction in thyroid adenoma |
Causes of thyroid hormone excess
Symptoms | Signs |
Irritability, Hyperactivity, Dysphoria | Tachycardia, Lone Atrial Fibrillation |
Heat Intolerance | Fine tremor |
Palpitation, Nervousness | Warm moist skin, Goiter |
Fatigue, lethargy | Proximal Myopathy |
Dyspnoea | Hyperreflexia |
Weight loss despite polyphagia | Lid lag, Lid tremors |
Hyperdefecation, Polyuria | Gynaecomastia |
Oligomenorrhoea | Loss of libido |
Common clinical features
Diffuse toxic goitre is commonly known as Graves’ disease. Classically it is characterized by hyperthyroidism and diffuse goiter. Graves’ disease may be associated with an infiltrative orbitopathy and ophthalmopathy and less commonly with an infiltrative dermopathy. Infiltrative orbitopathy is an unique manifestation of Graves’ disease.
Robert James Graves, an Irish physician, first described 3 females with this disease in 1835[1] and for his contribution, this disease is known as Graves’ disease in most part of the world. Although a similar syndrome was described by Caleb Hiller Parry, a physician from Bath, England, in 1825.[2] Carl A. Von Basedow from Germany first described the triad of exophthalmos, goiter and palpitation.[3] In most non English speaking European countries the disease is still known as Basedow’s disease.
Graves’ disease is the most common cause of thyrotoxicosis and it accounts for 60-80% cases of thyrotoxicosis. Prevalence of Graves’ disease varies with the degree of iodine sufficiency, and it is the most common cause of thyrotoxicosis in iodine sufficient countries.[4] High dietary iodine intake is associated with an increased prevalence of Graves’ disease. Prevalence of Graves’ disease is about 0.4% in USA,[5] 0.6% in Italy,[6] and 1.1% in UK.[7] A recent meta-analysis of various studies showed that prevalence of the Graves’ disease is about 1% in general population.[7] Prevalence of Graves’ disease is 1-2% in women, and it is about 10 fold more prevalent in women than men. Peak age of onset of Graves’ disease is in fourth to sixth decade of life[8], but it can occur in children and elderly.
Graves’ disease is a multifactorial disease in which genetic,environmental, and hormonal factors play their role.
High prevalence of Graves’ disease in family members and relatives of Graves’ disease and Hashimoto’s thyroiditis support that genetic factors are involved in causation of Graves’ disease. There is also evidence that occurrence rate of Graves’ disease is higher in monozygotic twins than dizygotic twins. The concordance rate in monozygotic twins is only 17-35% which indicate low penentrance of genes.
Graves’ disease is a polygenic disease. Polymorphism in HLA-DR, CTLA-4 and PTPN-22 genes are associated with increased risk of Graves’ disease. HLA-DR3 (HLA-DRB1*03), HLA-DQA1*0501 and HLA-B8 gives a risk ratio of three fold to fourfold in white population. HLA-DQ3 is involved in patients with African descent whereas HLA-BW46 is involved in patients with Asian descent. The other genes involved in pathogenesis of Graves’ disease are CD40 gene, thyroglobulin gene, TSHR gene, immunoglobulin genes, GD-1 gene (on chromosome 14q13), GD-2 gene (on chromosome 20) and GD-3 gene (on chromosome Xq21-22).
Infection
From very early it has been suggested that Graves’ disease is associated with infectious agents, but this hypothesis has not been confirmed. Incidence of recent viral infections are high in patients with Graves’ disease. The association of Graves’ disease with infectious agents can be explained by molecular mimicry. Molecular mimicry implies structural similarity between infectious agent with a self antigen. Circulating antibody against Yersinia enterocolitica has been found in high percentage of patients with Graves’ disease. Furthermore, serum from some patients recovering from Yersinia infections block the binding of TSH to its receptor. Low affinity binding sites for TSH have also been found with Leishmania and Mycoplasma species. However, no studies proved that infections agents have causative role in Graves’ disease.
Stress
In different studies, it has been found that stressful life events precedes the onset of Graves’ disease. Severe emotional and physical stress, like separation from the loved one or following road traffic accident, cause release of cortisol ad corticotrophin releasing hormone. So, stress is a relatively immune suppression state. Immune system overcompensates once stress is over which can precipitate disease similar to postpartum period. In conclusion there is limited but significant evidence that stressful life events can precipitate the onset of Graves’ disease in genetically susceptible individuals.
Gender
Typically Graves’ disease is more prevalent in females than males. It is about 5-10 times more common in females at any age. [6],[7] In children this difference is smaller. The exact cause for female preponderance is not known, but it is similar to other autoimmune disorders. In experimental animal models of autoimmune thyroiditis it has been seen that androgens appear to down regulate the immune system.[8],[9] Other possible explanation for female preponderance is female sex steroids. But Graves’ disease also occurs in men and postmenopausal women. These observations have suggested that it is the X-chromosome, not the sex steroids, which is responsible. But most of the x-linked disorders are only present in man, it has been thought that a gene with dose dependent effect on X-chromosome is responsible.
Pregnancy
Postpartum period is an important risk factor for both the onset and relapse of Graves’ disease. Postpartum period is associated with a fourfold to eightfold increased risk for the onset of Graves’ disease. Rebound immunity is the likely explanation for this increased risk. Graves’ disease is associated with low pregnancy rate because thyrotoxicosis decreases the fertility rate. However in women with Graves’ disease who became pregnant, successful pregnancy outcome is low because Graves’ disease causes increased pregnancy loss and its complications. Graves’ disease exacerbates during the first trimester of pregnancy and postpartum period, while it improves during the second and third trimester of pregnancy.
Smoking
Smoking is a minor risk factor for Graves’ disease; however it is a major risk factor for Graves’ ophthalmopathy. There are number of studies showing relationship between Graves’ disease, Graves’ ophthalmopathy and smoking. [11],[12]
Other risk factors:
Direct trauma to the thyroid gland, ethanol injection for the treatment of autonomously functioning thyroid nodules, or thyroid injury following radio-iodine treatment for toxic adenoma or toxic multinodular goiter are associated with an increased risk of Graves’ disease. Radio-iodine treatment may also cause onset or worsening of ophthalmopathy. Possible explanation is that thyroid injury by any means cause massive release of thyroid antigens, which in turn stimulate an autoimmune reaction to TSHR in susceptible individuals.
Graves’ disease onset and recurrence is also associated with iodine and iodine containing drugs like amiodarone and radio-contrast media especially in iodine deficient population.
Graves’ disease is an example of organ specific autoimmune disorder in which both humoral and cell mediated immunity directed against different thyroid antigens are involved. TSHR is the primary autoantigen of Graves’ disease, while other autoantigens like thyroglobulin and thyroid peroxidase are secondarily involved.
TSHR is a member of GPCR super family and involves cAMP and phosphoinositol pathways for signal transduction. TSHR has large intracellular domain (subgroup B). It is a glycoprotein consisting of 744 amino acids and having molecular weight of 84 kd. Gene for TSHR is located on chromosome 14q31 and is formed by 10 exons. Circulating autoantibody directed against the TSHR is the primary factor responsible for Graves’ disease. TSHR antibodies (TSHR-Ab) are of three types- namely stimulating antibody, blocking antibody and neutral antibody. Stimulating antibodies are those who after binding to TSHR activate adenylate cyclase and cause increased thyroid growth and vascularity, and increases the production of thyroid hormones. Blocking antibodies are those who after binding to TSHR act as an antagonist, whereas neutral antibodies does not have any functional activity.
Almost 50 years ago(in 1956) long acting thyroid stimulators (LATS) was discovered by Adams and Purves during a search for thyroid stimulating activity in patients with Graves\' disease. [13] Later on it was found that LATS are nothing but immunoglobulin of IgG1 subclass.
Transplacental transfer of TSHR stimulating antibodies (TSAb) from TSAb positive pregnant mother to fetus causes transient neonatal thyrotoxicasis that improves spontaneously after the disappearance of TSAb. [14] This provides the definite role of TSAb in the causation of Graves\' disease. TSAb are oligoclonal.
TSAb are produced mainly by the lymphocytes infiltrating the thyroid gland and lymphocytes present in the draining lymph nodes, and partly by the circulating blood lymphocytes.[15],[16] There is a positive correlation exists between the TSAb level and serum triiodothyronine level, serum thyroglobulin level and goiter size. TSAb are found in 90-100% of untreated Graves\' disease patients.[17], [18] Level of TSAb decreases after treatment with anti- thyroid drugs and radio-iodine.[19], [20]
Two types of assays are used for TSHR-Ab-Radioreceptor assays and invitro bioassays.
Radioreceptor assay is most readily available and most widely used in clinical practice. Basic principle of radioreceptor assay is displacement of labeled TSH from solubilized TSHR from patient\'s serum. This TSH- binding inhibitory immunoglobulins (TBII) assay does not provide information regarding the functionality of TSHR-Ab. TBII assays are cheaper and having good precision. The first generation TBII assays have sensitivity of 75-95% in untreated Graves\' disease patients. Most recently a monoclonal human antibody to TSHR is used. This second generation radio-receptor assay has sensitivity of 99% and very high specificity. [21]
In vitro bioassays are based on the ability of patients serum to stimulate adenylate cyclase and produce cAMP from cultured hamster ovary cells transfected with human TSHR (CHO-R),[23] or rat thyroid cell strain (FRTL-5)[24] or human thyroid follicular cells [25] are used as a source for functional TSHR. CHO-R system is slightly more sensitive, and requires an easier culture condition than other systems. Advantages of bioassays are that it gives information about the functional property of TSHR-Ab, but bioassays are more expensive, not widely available, having poor precision and sensitivity of more than 90%. These problems have been solved in newer bioassays.
The thyroid gland in Graves\' disease is characterized by non-homogenous lymphocytic infiltration. Majority of the intrathyroidal lymphocytes are T lymphocytes. B-lymphocytes are much less common than Hashimoto\'s thyroiditis. Cytokine profile produced by intrathyroidal T lymphocytes suggested that both TH1 & TH2 cells are present in thyroid. Majority of the T-lymphocytes are of TH1 subtype.[26],[27]
TH1 cells are mainly involved in delayed type of hypersensitivity reactions, and it produces the cytokines like TNF-B, IFN-Y, IL-2, IL-10 and IL-17. TH1 cells are implicated in the pathogenesis of organ specific autoimmune diseases that is mediated mainly by TNF-β subtype, which uniquely produces IL-17. TH 2 cells are mainly responsible for humoral immune responses and they produce cytokines like IL-4, IL-5, IL-6 and IL-13.TH1 cells may also induce antibody formation through secretion of IL-10 [28]. IgG1 subclass of antibody are selectively induced by TH1 cells. Most of the intrathyroidal T cells are of memory (CD4+, CD29+) subtype. Concentration of cytotoxic T cells (CD8+) are much less in Graves\' disease patients than patients of Hashimoto\'s thyroiditis. So the functional role of T cells in Graves\' disease is primarily a helper than a suppressor or cytotoxic role.
Structural or conformational similarity between different antigens like infectious agent with a self antigen can lead to crossover of specificity or molecular mimicry. Molecular mimicry has been reported between Reoviral antigen and a tissue antigen expressed in multiple endocrine tissues, Yersinia enterocolitica and TSHR, Retroviral sequences and TSHR & Borrelia and TSHR.
There is evidence that bystander activation of local resident antigen specific and nonspecific T- cells by a local viral infection would induce an inflammatory reaction and stimulates the production of cytokines induce autoimmunity. This bystander activation can also occur in any infections and antigens unrelated to the thyroid gland.
MHC class II molecules (HLA-DP, DQ, and DR) are not expressed on the normal thyroid epithelial cells but they are expressed on thyroid epithelial cells in patients of autoimmune thyroid disease. This aberrant expression of class II HLA antigens on thyroid epithelia cells can be induced by local thyroid insult which causes production of interferon γ and other cytokines. Interferon γ is able to over express HLA class I molecule and induce the expression of class II molecule on thyroid epithelial cells.
Autoimmunity results from the loss of tolerance or the ability to differentiate between self and non self. Tolerance induction is a staged process that initiates in the thymus during T-cell maturation. This process depends in part on the presence of peripheral antigens in the thymus. Peripheral antigens are antigens normally expressed in tissues outside of the immune system which are expressed at low levels in thymus. T cells that react strongly to these peripheral molecules in the context of MHC are deleted in thymus. T cells that react with peripheral antigens that are not expressed in the thymus have a greater opportunity to escape tolerance.
Hygiene hypothesis implies that infection may protect form autoimmune diseases rather than precipitating it. Decreased exposure to antigens due to improved living standards can lead to increased risk of autoimmune disorder.
Super antigens are endogenous or exogenous proteins such as microbial proteins, capable of stimulating a strong immune response through molecular interactions with non-variant parts of the T- cell repertoire and the HLA class II proteins.
Grossly the thyroid gland is diffusely enlarged with smooth and hyperemic surface. Rarely the gland is grossly nodular. Consistency of the gland varies from soft to firm. Pyramidal lobe is often prominent.
Microscopically both hypertrophy and hyperplasia are seen. Follicles are small with scanty colloid, and lined by hyperplasic columnar epithelium which can give a pseudopapillary appearance. Vascularity of the gland is increased. There is varying degree of infiltration by lymphocytes and plasma cells. T cells predominate in the interstitium, whereas B cells and plasma cells predominate in lymphoid follicles.
On electron microscopy there is increased golgi reticulum and mitochondria, and it is also characterized by presence of prominent microvilli.
After treatment with antithyroid drugs and radioiodine, the vascularity of the gland decreases, follicles enlarges and filled with colloid, and papillary projection regresses.
Graves\' disease is the most common cause of thyrotoxicosis. Most common age of onset is third to fourth decade of life but it can occur in children and elderly. The hallmark of Graves\' disease is signs and symptoms of thyrotoxicosis along with diffuse goiter and typical Graves\' orbitopathy. Most of the signs and symptoms are similar to other causes of thyrotoxicosis, but some of the signs and symptoms like orbitopathy, dermopathy or pretibial myxedema and thyroid acropachy are unique to Graves\' disease.
Onset of Graves\' disease is usually gradual. Signs and symptoms are presents months before the diagnosis, and usually patients do not remember the exact date of onset of symptoms. Onset can be abrupt in some cases. The signs and symptoms are usually more severe than other causes of thyrotoxicosis.
Thyroid gland is diffusely enlarged in Graves\' disease, but it can be nodular especially in areas of iodine deficiency where nodular goiter preexists before the onset of Graves\' disease. Goiter size is variable. It can range from normal size thyroid gland to massively enlarged thyroid. Usually size of goiter is two to three times that of normal. Normal size thyroid gland can the seen in as many as 20% of patients and most of them are elderly. The consistency of the goiter varies from soft to firm but softer than the goiter of Hashimoto\'s thyroiditis. Thrill and bruit can be present over goiter in severe cases and it is due to increased vascularity of the gland. Thrill and bruit are present usually on upper or lower pole and continuos in nature, but sometimes can present only in systole. Large goiter with intrathoracic extension can be associated with facial swelling and flushing, and neck vein distension upon raising the arm above the head. This is known as Pemberton sign.
Graves\' ophthalmopathy is one of the distinctive manifestations of Graves’ disease. Overall clinical ophthalmopathy is present in about 50% of Graves’ disease patients,[29] however CT or MRI reveals extraocular muscle enlargement in about 70% of patients without overt clinical ophthamopathy.[30],[31] Bimodal age distribution was noted for ophthalmopathy in both men and women. Peak age is 40 to 44 years and 60 to 64 years in women, whereas in men it is 45 to 49 years and 65 to 69 years.
There is no specific genetic predisposition for graves\' ophthalmopathy. Environmental factors are more important for ophthalmopathy.
Smoking
Smoking is a major risk factor for ophthalmopathy. Smoking also increases the risk for worsening of ophthalmopathy after radioiodine treatment. Possible contributors are orbital hypoxia and free radical present is smoke. [32],[33]
Gender
Graves’ disease is predominantly a disease of females (F: M= 8-10:1). In comparison to Graves’ disease, ophthalmopathy is relatively more common in males (F: M= 1:1.8-2.8) than females. [34],[35]
Radioiodine
Graves\' disease patients treated with radioiodine are at increased risk for onset and worsening of eye disease, as compared to antithyroid drugs alone. [36],[37] This risk can be decreased by concurrent use of corticosterodis.[38],[39]
Current evidence support an autoimmune pathogenesis with important environmental influences, particularly smoking. Orbital muscles, connective tissues, and adipose tissues are infiltrated by lymphocytes and macrophages. TH1 mediated immune response predominates in early stage of disease while TH2 response predominates in late stage. [40] In response to cytokines secreted by the infiltrating immune cells, orbital fibroblasts start synthesizing and secreting hydrophilic glycosaminoglycans, resulting in edema of orbital tissues. Additionally adipocytes present in orbit become active and results in expansion of orbital adipose tissues. Both these factors are responsible for expansion of orbital tissues.
Onset of eye disease usually coincides with that of thyrotoxicosis in 40% of cases, follow it in 40%, and precedes it in 20%.[41],[42] Even when the onset of the two disorders does not coincide, each occurs within 18 months from the onset of the first manifestation. Eye disease usually shows a progressive deterioration lasting for several months followed by a phase of spontaneous improvement lasting upto a year and longer and quiescent stage when inflammatory signs disappear and clinical features stabilizes.
The earliest manifestations of ophthalmopathy are usually a sensation of grittiness, eye discomfort, and excess tearing. Other common symptoms are spontaneous retroorbital pain, pain on ocular movement and diplopia. Diplopia is most common in upgaze or in extremes of lateral gaze, because of the involvement of inferior or lateral rectus muscle. About one third of patients have proptosis which can best be detected by visualization of the sclera between the lower border of iris and the lower eyelid when the eyes are kept in primary position.
In severe cases proptosis can cause exposure keratitis and corneal ulcerations. Proptosis is frequently assymetrical. Retraction of the upper eyelid and less commonly of lower eyelid results in lid lag, globe lag, and lagophthalmos. Movements of the lids are jerky, and also there is tremor of lightly closed eyes. These are the non specific manifestations of thyrotoxicosis. Other signs and symptoms are photophobia, swelling of the eyelids, blurring of vision, conjunctival injection and chemosis, periorbital edema.
Decreased visual acuity and color vision, corneal ulceration, and subluxation of globe are present in most severe cases. Blindness may result from corneal ulceration and compression of the optic nerve at the orbital apex due to increased orbital pressure and venous congestion.
Graves\' ophthalmopathy can occur in absence of Graves\' disease in 10% cases, that’s why it is also known as thyroid associated ophthalmopathy, or euthyroid Graves’ opthalmopathy. Graves\' ophthalmopathy is usually bilateral but it can be unilateral in upto 10% cases.
The acronym NO SPECS was given by American Thyroid Association for severity of ophthalmopathy, where no indicates absence or mild ophthalmopathy, and SPECS indicates more severe degree of involvement, but NO SPECS scheme is inadequate and patients do not necessarily progress from one class to other.
Classes | Ocular symptoms and signs |
0 | No signs and symptoms |
1 | Only signs (lid retraction, lid lag, proptosis upto 22 mm) |
2 | Soft tissue involvement (periorbital edema) |
3 | Proptosis ("/>22 mm) |
4 | Extraocular muscle involvement (diplopia) |
5 | Corneal involvement |
6 | Sight loss (optic nerve involvement) |
To know the clinical activity of ophthalmopathy is important, because active disease is more likely to respond to immunosuppressive therapy. Clinical Activity Score (CAS) is used to know the clinical activity. Seven parameters are used in the clinical activity scoring which include spontaneous retrobulbar pain, pain on eye movement, eyelid erythema, conjuctival injection, swelling of the eyelids, inflammation of the caruncle and conjunctival edema or chemosis. Each parameter is assigned 1 point. CAS of more than or equal to 3/7 indicates active ophthalmopathy.
Thyroid dermopathy presents in less than 5% of patients with Graves’ disease. It is almost always accompanied by moderate to severe ophthalmopathy. Most commonly it is present over anterior and lateral aspects of leg, hence it is also known as pretibial myxoedema. Less commonly it can present over dorsa of the feet, dorsa of the hands, forearm, face and elbows, particularly after trauma. The typical lesion is a noninflamed, indurated plaque with a deep pink or purple color and an orange skin appearance. Nodular form is the intermediate while elephantiasis is the most severe form of thyroid dermopathy. Thyroid dermopathy occurs due to accumulation of glycosaminoglycans in the dermis and subcutaneous tissues.
Thyroid acropachy is the least common manifestation of Graves\' disease. It is a form of clubbing, and presents in less than 1 percent of patients of Graves\' disease. It is almost always associated with the severe and long standing ophthalmopathy and dermopathy. An alternate diagnosis should be considered in the absence of ophthalmopathy and dermopathy. Deposition of glycosaminoglycans in skin is responsible for thyroid acropachy.
Diagnosis of Graves\' disease can be confirmed by measurement of serum TSH and total thyroxine (TT4) and triiodothyronine (TT3). Serum TSH level is suppressed or undetectable with increased TT4 and TT3 level in patients of Graves\' disease. Serum TSH level is the most sensitive test. The free T4 (FT4) and free T3 (FT3) levels are increased more than that of TT4 and TT3. Measurement of FT4 and FT3 are expensive, and there is more chance of laboratory errors. FT4 and FT3 can be measured in conditions associated with high serum TBG level like pregnancy, oral contraceptive use and chronic liver disease. In patients of Graves\' disease serum T3 level is proportionately more elevated than the serum T4 level. In upto 12% of patients, especially in the iodine deficient areas, only TT3 or FT3 is elevated with a normal TT4 or FT4 level, a condition known as T3 toxicosis. Conversely in some patients (iodine induced hyperthyroidism, drugs like amiodarone and propronolol which block the conversion of T4 to T3), only TT4 or FT4 is elevated with normal TT3 and FT3 (T4 toxicosis). Serum thyroglobulin level is high in all cases of thyrotoxicosis except factitious thyrotoxicosis.
Anti TPO antibody can be detected in upto 90%[43],[44] of patients with Graves\' disease whereas anti-thyroglobulin antibody is present in 50-80% cases.[45],[46] They are useful in confirming the presence of thyroid autoimmunity but they are of limited diagnostic value. TSHR-Ab assay is very sensitive and specific (upto 98%) for the diagnosis of Graves\' disease. But TSHR-Ab assay is quite expensive and not widely available. TSHR-Ab assay is indicated only when clinical and laboratory diagnosis are not clear. Indications for TSHR-Ab assay are:
Euthyroid Graves\' disease, especially when it is unilateral
Pregnant women with Graves\' disease to predict the likelihood of neonatal thyrotoxicosis
Nodular variant of Graves\' disease
TSHR-Ab assay is also a useful indicator of the degree of disease activity. It can also predict the prognosis of Graves\' disease. There is more chance of relapse in patients with persistently high TSHR-Ab level after cessation of antithyroid drug.[47]\n\t\t\t
Associated hematological abnormalities include increased RBC mass, leucopenia with relative lymphocytosis, monocytosis and eosinophilia, increased factor VIII level. Other associated abnormalities include elevated liver enzymes, bilirubin and ferritin.
RAIU is not required in each and every case of Graves\' disease, but it is useful in excluding thyrotoxicosis caused by thyroiditis, factitious thyrotoxicosis, and type II amiodarone induces thyrotoxicosis. RAIU is absolutely contraindicated in pregnancy. In Graves\' disease RAIU is diffusely increased.
In Graves\' disease thyroid tissue typically become hypoechoic because of reduction in colloid content, increase in thyroid vascularity and lymhocytic infiltration. In colour flow doppler there is a distinct pattern characterized by markedly increased signals, inferior thyroid artery and itrathyroidal artery velocities more than 40 cm/s. This pattern, in conjunction with a hypoechoic pattern allows distinction from Hashimoto\'s thyroiditis.
If a patient presented with diffuse goiter with clinical and biochemical thyrotoxicosis, ophthalmopathy and positive autoimmune markers like anti TPO antibody or TSHR-Ab, diagnosis of Graves\' disease is straight forward. In absence of these classical features radionuclide scan (I123, I131, Tc99m) in the most reliable distinguishing test. In case of Graves\' disease there is diffuse and high uptake, whereas in patients with toxic adenoma or toxic multinodular goiter there is patchy uptake. In patients with thyroiditis and factitious thyrotoxicosis there is decreased uptake. In patients with TSH producing adenoma, there is also a diffuse goiter, but TSH is inappropriately normal or increased instead of suppress TSH of graves\' disease. Panic attacks, mania, pheochromocytoma and malignancy can be easily ruled out by thyroid function test.
There is no ideal treatment option present targeting the basic pathogenic mechanisms of Graves\' disease. Available treatment options target the increased synthesis of thyroid hormones by antithyroid drugs, or ablation of thyroid tissue by surgery or radioiodine. Antithyroid drugs are the predominant therapy in Europe and Japan whereas radioiodine is first line of treatment in USA. No single treatment is optimal and patients often require multiple treatment.
Thionamides are the main antithyroid drugs which includes propylthiouracil, carbimazole and methimazole. Thionamides act by inhibiting the enzyme thyroid peroxidase, reducing the oxidation and organification of iodide and coupling of iodotyrosines. Carbimazole is not an active drug, and in body it is converted to active metabolite methimazole. Proylthiouracil, in addition to inhibit thyroid hormone synthesis, also inhibits the peripheral conversion of T4 to T3. Methimazole is ten times more potent than prophylthiouracil. Half life of methimazole is about 6 hours while that of prophylthiouracil is about 90 minutes. Duration of action of methimazole is more than 24 hours while that of propylthiouracil is 12-24 hours. Transplacental transfer of prophylthiouracil is lowest. Antithyroid drugs do not block the release of preformed hormones, so euthyroidism is not obtained until intrathyroidal hormone store is depleted. These drugs also reduce thyroid antibody level.
Antithyroid drugs can be used as a primary treatment or as a preparatory treatment before radioiodine or surgery. The antithyroid drugs are usually started in higher doses. The starting dose of methiomazole or carbimazole is 10-20 mg every 8-12 hours and that of propylthiouracil is 100-200 mg every 6-8 hours. Once euthyroidism is achieved which usually takes 4-5 weeks, methimazole can be given in single daily dose while propylthiouracil is given in multiple daily doses throughout the treatment. There are two treatment strategies for using antithyroid drugs. In titration regimen, antithyroid drugs are started in high doses and dose can be gradually decreased to maintain euthyroid state. In Block and Replace regimen, the antithyroid drugs are maintained in high doses and subsequently levothyroxine is added to maintain the euthyroid status. At present there is no proven advantage of block and replace regimen over titration regimen.
Patient should be reviewed clinically and biochemically after every 3-4 weeks. Dose of antithyroid drugs is adjusted based on the TT4 or FT4 level, as TSH level often remain suppressed for several months. The usual daily maintenance dose of carbimazole or methimazole is 2.5 – 10 mg and that of propylthiouracil is 50-100 mg. When TSH level become normal, it can also be used to monitor therapy. Size of the goiter decreases in about 30-50% of patients during treatment. In remaining patients it may remain unchanged or even enlarge. Increase in goiter size is one of the earliest manifestations of iatrogenic hypothyroidism. The other features are weight gain, lethargy, fatigue and other signs of mild hypothyroidism.
Maximum remission rate with antithyroid drugs is 30-50%, which can be achieved by continuation of the drug for 6-18 months or even longer. Most of the relapses occur within first 3-6 months after discontinuation of drug. Suppressed TSH level below the normal limit is the first signal of relapse even in the presence of a normal serum T4 level. In most of the studies, the relapse rate is 50-80%.[48],[49] Most important predictor of relapse is goiter size.[50] Other factors influencing recurrence of Graves\' disease include high TSHR-Ab concentration, large iodine intake, marked residual goiter, short duration of antithyroid drug treatment and previous recurrence. Factors which favor long term remission after therapy include the initial presence of T3 toxicosis, a small goiter, decrease in the size of goiter, and return of TSH to normal during treatment, the return of serum thyroglobulin to normal, and low iodine diet.
Most common side effects of thionamides are pruritus, skin rash, urticaria, fever and arthralgia. These may resolve spontaneously or after substituting another drug. Rare but major side effects are hepatitis, cholestasis, SLE like syndrome, ANCA positive vasculitis and most importantly agranulocytosis. Major side effects occur in less than 1% of patients.Antithyroid drugs should be stopped and not restarted if patient develop major side effects.
Inorganic iodine acts in many ways in thyrotoxicosis. Iodine blocks its own transport in thyroid, inhibits iodine organification and inhibits the release of hormone. Inhibition of iodine organification by inorganic iodide is known as Wolf-Chaikoff effect. Major action of iodine is inhibition of hormone release. Iodine also decreases the vascularity of thyroid gland. All of these effects of iodine are transient and lasts only for a few days or weeks. Now a days iodine is used only for preoperative preparation for Graves’ disease and in the management of thyrotoxic crisis. The usual dose of Lugol\'s solution is 3-5 drops three times per day and that of SSKI is 2-3 drops twice daily. Iodine decreases the effect of subsequently administad thionamides and radioiodine for severe weeks.
Iodinated radio contrast agents like iopanoic acid, and sodium ipodate acts by blocking the peripheral conversion of T4 to T3 and inhibition of hormone release. They are ideally used in emergency situations when rapid control of thyrotoxicosis is needed or in preoperative preparation or while awaiting the response of radioiodine.
They act by intititing the transport of iodine to thyroid gland.
Lithium also acts as a thyroid constipating agent (block the release of thyroid hormones). Lithium also potentiates the beneficial effect of radioiodine. The usual dose of lithium is 450-900 mg per day in divided doses. Serum lithium concentration should be maintained at 1meEq/L. No adverse effects are reported with this dose of lithium.
Dexamethasone in high doses (8mg/day) decreases the T4 secretion by the thyroid gland, inhibit the peripheral conversion of T4 to T3, and has immunosuppressive effect. Effect on peripheral conversion of T4 to T3 is additive to propylthiouracil. Glucocorticaids are indicated for the treatment of ophthalmopathy, dermopathy and in thyrotoxic crisis.
β- blockers do not affect the synthesis or secretion of thyroid hormones. Many of the symptoms & signs of thyrotoxicosis are due to hypersensitivity of the sympathetic nervous system to thyroid hormones. Thus use of β- blockers in thyrotoxicosis, improve the signs and symptoms mediated by the sympathetic nervous system. Tachycardia, palpitation, tremor, anxiety, excess sweating, lid retraction improves with β- blockers. Propranolol has additional advantage over other β- blockers. It inhibits the peripheral conversion of T4 to T3. β- blockers reduce cardiac output without altering oxygen consumption, can have adverse effect in liver, where the arteriovenous oxygen difference is already elevated in the hyperthyroid state. Propranolol is most commonly used agent but other β- blockers can also be used. It is used in a dose of 20-60 mg every 6-8 hours. Short acting agents like esmolol is used for intravenous purpose. Long acting agents like atenolol or metoprolol are used for prolonged treatment. β- blockers should be rapidly tapered and discontinued once stable euthyroidism it achieved.
Radioiodine is one of the first line therapy for the Graves\' disease. Among different isotopes of radioiodine, I131 is the agent of choice. I131 is a β-emitter isotope. After oral administration, I131is completely absorbed and rapidly concentrated in thyroid follicular cells. β- particles, which are emitted by I131, destroy the thyroid follicular cells that results in reduced thyroid hormone synthesis. Initially destruction of thyroid follicular cells results in release of preformed hormones that can precipitate the thyortoxic crisis. Weeks to months are required for control of thyrotoxicosis. Long term effects of radioiodine include atrophy and fibrosis, and a chromic inflammatory response resembling Hashimoto\'s thyroiditis.
Radioiodine is given as single oral dose. Three outcomes of radioiodine treatment are possible- patients become euthyroid or remain thyrotoxic or become permanently hypothyroid. Dose of radioiodine depends on the size of gland, the uptake of I131 and its subsequent rate of release. Dose of radioiodine ranges from 80-200 μCi/gm of thyroid tissues. A total dose of 20 mCi achieves thyroid ablation in almost all patients and results in permanent hypothyroidisms in 75-90% of patients. [51] The incidence of post radioiodine hypothyroidism in first year is 25% and steadily increases thereafter at a rate of 5% per year. When required, the second dose of radioiodine should be given at least 6 months after the first dose. Failure of radioiodine treatment is more common in patients with large goiter, rapid iodine turnover and adjunctive antithyroid drugs too soon after radioiodine. Prior use of antithyorid drugs decreases the risk of thyrotoxic crisis. Chance of worsening ophthalmopathy can also be reduced by antithyroid drugs. Antithyroid drugs should be stopped 3 to 8 days prior to radioiodine treatment and should be restarted after 7 days when required. Propylthiouracil may cause radio-resistance, but it not a major concern. Short term side effects of radioiodine include transient exacerbation of thyrotoxicosis in the first few months, transient worsening of ophthalompathy, acute radiation thyroids in the first week. Radiation thyroidits may lead to transient worsening of thyrotoxicosis and ophthalmopathy. Presence of mild to moderate ophthalmopathy is not a contraindication for radioiodine treatment. Concomitant use of oral glucocorticoids, decreases the risk of worsening ophthalmopathy. Long term side effect of radioiodine is permanent hypothyroidism. Initially there was a concern regarding possible carcinogenic effect and risk of genetic damage after radioiodine treatment. But now it is proven that there is no association between radioiodine treatment and thyroid carcinoma, leukemia, solid tumors and genetic damage.[52] Thyroid cancer is associated with low dose of I131 rather than higher dose of I131 in children. [53] Some centers uses radioiodine even in children of 10 years of age or younger, but still there is no consensus regarding use of radioiodine for persons younger than 16 to 18 years.
Surgery is a form of ablative therapy. Enough thyroid tissue is removed by surgery to reduce the synthesis of thyroid hormones and prevent recurrence. Two type of thyoid surgery are used for Graves\' disease. In subtotal thyroidectomy, bulk of the thyroid gland is removed and only about 2 gm (0.5%) of thyroid tissue is left in both lobes. In near total thyroidectomy, most of the thyroid gland is removed, with only subcentimeter fragment are left around recurrent laryngeal nerve and parathyroid glands. Subtotal thyroidectomy was the procedure of choice in past, but it is associated with higher recurrence rate. Now-a-days near total thyroidectomy is used most often. Near total thyroidectomy is associated with more chance of permanent hypothyroidism but less chance of recurrence than subtotal thyroidectomy.
Complications of thyroid surgery depends on the skill and experience of operating surgeon. In specialized hands, complication rate is as low as 2%, whereas complication rate increases up to 10-15% in non specialized centers. Post Operative bleeding is the most serious complication. It can be fatal by producing asphyxia, if it is not evacuated immediately. Other complications like thyroid storm, injury to recurrent laryngeal nerve and hypoparathyroidism are specific to thyroid surgery. Thyroid storm is rare now-a-days. Injury to recurrent laryngeal nerve causes dysphonia, that usually improves with time, but that may leave the patient slightly hoarse. Hypoparathyroidism can be transient or permanent. Transient hypoparathyroidism is due to removal of the some parathyroid and impairment of blood supply to parathyroid glands, whereas permanent hypoparathyroidism is due to inadvertent removal of all 4 glands. Transient hypoparathyroidism usually occur on day 1-7 postoperatively. Severe symptomatic hypoparathyroidism should be treated by intravenous calcium gluconate. Oral calcium (upto 3 gm/day) is sufficient for milder cases. Immediate postoperative hypocalcemia is due to hungry bone syndrome. Recurrence of hyperthyroidism and permanent hypothyroidism are inversely related and depends on the amount of thyroid tissue left. In case of recurrence, radioiodine should be used as treatment, as second surgery is technically difficult.
Preoperative preparation
Preoperative use of thionamides is associated with lesser morbidity and mortality. Preoperative thionamides are recommended to achieve euthyroidism and to deplete. The hormone store. Preoperative use of inorganic iodine decreases the gland size and vcascularity. In case of emergency surgery oral cholecystographic agents are the fastest way to obtain euthyroidism. The goal of preoperative management is to maintain euthyroid states by thionamides and then to induce involution of the gland by the inorganic iodine. β blockers can be used in preoperative preparation.
Choice of therapy
Choice of therapy depends on the patient preference, personal experience of the treating doctor and availability of the treatment options. All the three treatment options (antithyroid drugs, radioiodine, surgery) can be used as first line therapy. In most of the Europe, antithyroid drugs are the preferred treatment whereas in USA, radioiodine is the preferred treatment. Primary choice of treatment in children and young adults upto 18 years of age is antithyroid drugs, although radioiodine is not associated with any adverse events. Pregnancy should be delayed for 6-12 months after radioiodine treatment. Presence of severe ophthalmopathy is a contraindication for radioiodine treatment. Surgery is the preferred treatment for patients with large goiter, especially if compressive symptoms are present, endemic goiter with multiple cold nodules, and suspected malignancy.
Thyroid ophthalmopathy
Mild to moderate ophthalmopathy does not require any specific treatment. General measures include control of thyrotoxicosis, smoking cessation, dark glasses with side frame for photophobia and sensitivity to air, artificial tear (1% methyl cellulose) or eye ointment for eye discomfort and dry eye, eye patches or taping during sleep for lagophthalmos, elevation of the head end for periorbital edema, prism for correction of mild diplopia.
Other patients with more severe signs and symptoms affecting daily lives to a significant extent may benefit from immunosuppressive therapy in active disease or surgical decompression in case of inactive disease. Severe ophthalmopathy with optic neuropathy and corneal ulcer is an emergency.
Glucocorticoids
Oral glucocorticoids is initiated at a relatively high dose, such as 40-80 mg of prednisolone per day. After 2-4 weeks, the daily dose is tapered by 2.5-10 mg every 2-4 weeks. Improvement in soft tissue inflammation begins within 1-2 days. Intravenous methylprednisolone pulse therapy is more effective and better tolerated than oral prednisolone.[54] 500 mg of methylprednisolone per week for 6 weeks followed by 250 mg of methylprednisolone per week for 6 weeks is most commonly used regimen. Cyclosporine can also be used either as a single therapy or in combination with oral prednisolone. Combination therapy of cyclosporine with prednisolone is more effective than either drug alone.[55]
Orbital Radiotherapy
Orbital radiotherapy is well tolerated and provide benefit in approximately two third of patients. This treatment is steroid sparing rather than steroid replacing therapy.
Other immunomodulatory therapy
Rituximab, azathioprine, cyclophosphamide, ciamexon, pentoxifylline and intravenous immunoglobulins have some benefit and are currently under trial.
Orbital decompression
Indications for orbital decompression include optic neuropathy, severe proptosis, vision threatening ocular exposure, debilitating retrobulbar and periorbital pain and intolerable corticosteroid side effects. Transantral orbital decompression with removal of a portion of medial wall and the orbital floor is most commonly used procedure. Upto 5 mm reduction in proptosis can be achieved by orbital decompression. Orbital decompression can cause onset or worsening of diplopia.
Thyroid storm
Thyroid storm or thyrotoxic crisis is a life threatening exacerbation of hyperthyroidism. Most of the cases of thyroid storm are associated with Graves\' disease, but it can also occur with toxic multinodular goitre. Precipitating factor for thyroid storm include infection, trauma, thyroid surgery, radioiodine, diabetic ketoacidosis, stroke etc. It can present with fever, tachycardia, arrhythmias, profuse sweating, diarrhea and vomiting, confusion, delirium, seizures, jaundice, coma, congestive heart failure, hypotension. Thyroid storm is associated with very high mortality rate (upto 30%, even with treatment).
Treatment of thyroid storm requires strict monitoring and proper care. Precipitating factors should be identified and treated. Supportive treatment include cooling blankets and drugs like acetaminophen, chlorpromazine or meperidine for hyperthermia, oxygen inhalation, intravenous fluids. Antithyroid drug of choice is prophylthiouracil but carbimazole can also be used. Prophylthiouracil 600 mg is given as loading dose by mouth or nasogastric tube or per rectum followed by 200-300 mg every 6-8 hourly. One hour after the first dose of propylthiouracil, stable iodide is given in the form of SSKI (3 drops twice daily) or Lugol\'s iodine (10 drops twice daily). Propranolol should also be given in a dose of 40-80 mg orally every 6 hours or 2 mg intravenously every 4 hours. If β blockers are contraindicated, calcium channel blockers like diltiazem can be used to control tachycardia. Large dose of dexamethasone (8 mg) by oral or intravenous route should be given to block the release of hormone from gland and peripheral conversion of T4 to T3.
The biliary ileum is defined as a mechanical intestinal obstruction due to the impact of one or more gallstones in the gastrointestinal tract and is a rare complication of cholelithiasis. The term “ileum” is an improper term, since obstruction is a true mechanical phenomenon [1, 2], while gastrointestinal obstruction from gallstones would be an appropriate term. Biliary ileum is not very common and diagnosis and treatment can be problematic.
\nBiliary ileus causes 1–4% of all cases of obstruction of the small intestine. This is 25% in patients over 65 years of age and is responsible for about three of the 10 million admissions to hospital and 15 for about 1 million surgical procedures (0.0015%). It is more common in women than in men with a 5:1 female-to-male ratio.
\nThe biliary ileum is often preceded by an initial episode of acute cholecystitis. Inflammation in the gallbladder and surrounding structures leads to the formation of adhesion. Inflammation and the pressure effect of gallstones causes erosion through the gallbladder wall, leading to the formation of fistulas between the gallbladder and the adiacent portion of the gastrointestinal tract, with further passage of gallstones [3, 4]. Less commonly, a gallstone can enter the duodenum through the common bile duct and through a dilated papilla of Vater [5]. The most frequent fistula occurs between the gallbladder and the duodenum due to their proximity [6, 7, 8, 9]. The stomach, small intestine, and transverse portion of the colon may also be involved (Table 1) [1, 2, 3, 4, 10, 11].
\nType of fistula | \n(%) | \n
---|---|
Colecystoduodenal | \n32.5 to 96.5 | \n
Colecystogastric | \n0 to 13.3 | \n
Colecystoduodenal | \n0 to 2,5 | \n
Colecystoileal | \n0 to 2,5 | \n
Colecystocolic | \n0 to 10.9 | \n
Frequency of bilio-enteric fistulas in patients with ileus from gallstones.
Once inside the duodenal, intestinal, or gastric lumen, gallstones usually proceed distally and can pass spontaneously through the rectum, or they can cause obstruction. Less commonly if the bile stone is in the stomach, proximal migration can occur and the bile stone can be vomited [4]. The size of the gallstones, the site of fistula formation, and the intestinal lumen will determine whether or not intestinal obstruction will occur. Most gallstones less than 2–2.5 cm can pass spontaneously through a normal gastrointestinal tract and will be excreted in the stool without problems [1, 2, 3, 4]. Clavien et al. [12] reported that an obstructive gallstone size ranges from 2 to 5 cm. Nakao et al. [6] found that gallstones had sizes ranging from 2 to 10 cm, with an average of 4.3 cm. The obstruction site can be found in any portion of the gastrointestinal tract. If gallstones enter the duodenum, the most common intestinal obstruction will be the terminal ileum and ileocecal valve due to their relatively narrow lumen and potentially less active peristalsis. Less frequently, gallstones obstruct the proximal ileum or jejunum, especially if the gallstones are large enough. Less common positions include the stomach and duodenum (Bouveret syndrome) and colon (Table 2) [1, 3, 4, 8, 9, 13].
\nPlace | \n% | \n
---|---|
Duodenum | \n0-10.5 | \n
Stomach | \n0-20 | \n
Proximal ileus | \n0-50 | \n
Distal ileus | \n0-89.5 | \n
Colon | \n0-8.1 | \n
Undetermined | \n0-25 | \n
Place range (%).
The presence of diverticula, neoplasms, or intestinal stenoses secondary to Crohn’s disease, reduce the size of the lumen and can cause an occlusion of gallstones on the narrowing site [1, 2, 3, 14]. Biliary ileum has been reported at anastomosis sites after partial gastrectomy and Billroth II reconstruction and after biliointestinal bypass in two cases [15, 16]. Ischemia can develop at the occlusion site of gallstones due to the pressure generated against the intestinal wall and proximal distension. Necrosis and perforation may occur followed by peritonitis [3]. The presentation of the biliary ileum may be preceded by a history of previous biliary symptoms, with rates ranging between 27 and 80% of patients [7, 12, 13, 17, 18, 19]. Acute cholecystitis can be present in 10–30% of patients at the time of intestinal obstruction. Jaundice was found in only 15% of patients or less. Bile symptoms can be absent in up to a third of cases [1, 2, 3, 8, 9, 12, 20, 21].
\nThe biliary ileum can manifest itself as an acute, intermittent, or chronic episode of gastrointestinal obstruction. Nausea, vomiting, cramping abdominal pain, and variable distension are commonly present [1, 3, 8, 12, 13, 20, 22, 23, 24, 25, 26, 27, 28, 29]. The intermittent nature of pain and vomiting of the proximal gastrointestinal material, which later becomes dark and fecaloid, is due to partial or total occlusion of gallstones [5, 18]. The character of vomiting depends on the location of the obstruction. When gallstones are in the stomach or upper small intestine, vomiting is mainly gastric in content (becoming fecaloid when the ileum is obstructed). In particular, Bouveret’s syndrome presents signs and symptoms of gastric outlet obstruction. Nausea and vomiting were reported in 86% of cases, while abdominal pain or discomfort was reported in 71%. If the bile stone does not completely obstruct the lumen, the presentation will be partially obstructed. Recent weight loss, anorexia, early satiety, and constipation can be reported by the patient. Bouveret syndrome has also been reported to be preceded by bleeding of the upper gastrointestinal tract secondary to duodenal erosion caused by gallstones, with hematemesis and melena, respectively, in 15 and 7% [8, 9, 30, 31]. The physical examination can be nonspecific. Patients are often seriously ill, with signs of dehydration, abdominal distension, and decrease in intestinal peristalsis and obstructive jaundice. Fever, toxicity, and physical signs of peritonitis can be noted if perforation of the intestinal wall occurs. The examination can be completely normal if no obstacles are currently present [1, 2, 3, 4, 30].
\nThe symptoms and signs of the biliary ileum are mostly nonspecific [7, 26, 29]. The intermittence of symptoms could also interfere with a correct diagnosis, if the clinical manifestations at the moment correspond to a partial obstruction or a distal migration of the gallstones. Patients usually present 4–8 days after the onset of symptoms, and diagnosis is usually made 3–8 days after the onset of symptoms [1, 2, 29, 32, 33, 34, 35, 36, 37, 38]. A high index of suspicion will be useful, particularly in an elderly patient with intestinal obstruction and previous gallstone disease; Bouveret syndrome can be suspected in a patient with gastric outlet obstruction.
\nSimple abdominal radiographs are of fundamental importance for establishing the diagnosis. In 1941, Rigler et al. [39] described four radiographic signs in the biliary ileum: (1) partial or complete intestinal obstruction; (2) pneumobilia or contrast material in the biliary tree; (3) an aberrant limestone; and (4) changing the position of such gallstones on serial film. The presence of two of the first three signs was considered pathognomonic and was found in 20–50% of cases [1, 2, 20, 37, 38, 40, 41, 42, 43, 44]. Although pathognomonic, Rigler’s triad ratios range from 0 to 87% [19]. Careful inspection for pneumobilia should be performed, as it is present in most patients with biliary ileus but is sometimes identified only in retrospective observation [20, 37, 38, 41, 42, 43]. Pneumobilia can occur following previous biliary surgery or endoscopic interventions. Therefore, clinical evaluation must be taken into account when evaluating this radiological sign [1, 2, 37, 38, 40, 41, 42, 43, 44]. In 1978, Balthazar et al. [45] described a fifth sign, which consists of two hydro-plane levels in the upper right quadrant of the abdominal radiography. The medial air fluid level corresponds to the duodenum and the lateral level to the gallbladder. These authors found that this sign was present in 24% of patients at the time of hospitalization. In Bouveret’s syndrome, a dilated stomach is expected to be seen on a simple abdominal radiograph due to gastric obstruction [37, 42, 43, 46, 47, 48, 49]. Cappell et al. [31], in a review of 64 cases of Bouveret syndrome, found pneumobilia (39%), calcified upper right quadrant mass or gallstones (38%), and gastric distension (23%) as relatively common findings and dilated loops of the intestine (14%).
\nWhen the diagnosis is still doubtful, an abdominal ultrasound (US) will be indicated for gallbladder stones, fistula, and gallstones visualization. It can also confirm the presence of choledocholithiasis [1, 2, 50]. The use of ultrasound in combination with abdominal radiography has been recommended to increase the sensitivity of the diagnosis. Ultrasound is more sensitive to the detection of pneumobilia and ectopic gallstones. The combination of abdominal and US radiography increased the sensitivity of the diagnosis of the biliary ileum to 74% [51]. The most frequent findings in Bouveret syndrome are gallstones in the gallbladder (53%), pneumobilia or gallbladder fistula (45%), gallstones in the duodenum (25%), dilated or distended stomach (15%), and a contracted gallbladder (13%) [31, 41, 43, 52, 53].
\nComputed tomography (CT) is considered superior to abdominal radiography or US in the diagnosis of biliary ileum cases, with a sensitivity of up to 93% [47, 51, 54, 55, 56, 57]. The detection frequency of Rigler’s triad is higher during the CT exam. In a retrospective study by Lassandro et al. [55, 56, 57, 58], the Rigler triad was observed in 77.8% of cases by CT, compared to 14.8% with radiographs and 11.1% with the US. Intestinal loop dilation was observed in 92.6% of cases, pneumobilia in 88.9%, ectopic gallstones in 81.5%, hydroaero levels in 37%, and bilio-digestive fistula in 14.8%. Yu et al. [54, 59] conducted a prospective study in which 165 patients with acute small bowel obstruction were evaluated for biliary ileus, with retrospective identification of three diagnostic criteria: (1) small bowel obstruction; (2) ectopic gallstones, both calcified and removed; and (3) abnormal gallbladder with complete air collection, presence of hydro-aircraft levels, or fluid accumulation with irregular wall. The overall sensitivity, specificity, and precision were 93, 100, and 99%, respectively. Rigler’s triad was detected only in 36% of cases. These tomographic diagnostic criteria require further prospective validation. Current CT scanners can describe the position of the fistula, gallstones, and gastrointestinal obstruction with greater precision helping in therapeutic decisions [37, 56, 57, 58].
\nIn an 81-case review of Bouveret syndrome [37, 43, 59, 60, 61, 62] in which esophagogastroduodenoscopy (EGD) was performed, gastroduodenal obstruction was revealed in all, but visualization of gallstones was only possible in 56 (69%). Among these 56 cases, such gallstones were observed in the duodenal bulb in 51.8%, in the postbulbar duodenum in 28.6%, in the pylorus or in the prepilorum in 17.9%, and in one case the position was not reported. Gallstones were not recognized in 31% of cases because they were deeply embedded in the mucosa. When gallstones are not displayed, the diagnosis should be strongly suspected when the observed mass is hard, convex, smooth, non-friable and non-fleshy, which are all characteristics of a biliary calculus and can improve the sensitivity of the EGD. For such cases, US and CT are the preferred noninvasive diagnostic tests to confirm endoscopic diagnosis, delineate gastroduodenal anatomy, and demonstrate a cholecystoduodenal fistula [27, 31, 52, 53, 63, 64, 65].
\nThe main therapeutic goal is the relief of intestinal obstruction by extraction of gallstones. Hydroelectrolytic imbalances and metabolic disorders due to intestinal obstruction and preexisting comorbidities are common and require management before surgery [1, 2, 14, 29, 31, 52, 53, 66, 67, 68].
\nThere is no unanimous consensus on the surgical procedure. Current surgical procedures are: (1) simple enterolithotomy; (2) enterolithotomy, cholecystectomy and closure of the fistula (one-stage procedure); and (3) enterolithotomy with cholecystectomy performed subsequently (two-stage procedure). Intestinal resection is necessary in some cases after performing the enterolithotomy.
\nEnterolithotomy was the most commonly performed surgical procedure. Through an exploratory laparotomy, the gastrointestinal obstruction site is located. A longitudinal incision is made on the antimesenteric edge proximal to the site of obstruction of the gallstones [12, 24, 66]. Whenever possible, through light manipulation, the bile stone is brought proximally to a non-edematous segment of the intestine. Most of the time, this is not possible due to the degree of impact of gallstones. Enterotomy is performed over the gallstones and extracted. Careful closure of the enterotomy is necessary to avoid narrowing of the intestinal lumen and cross-closure is recommended. Intestinal resection is sometimes required, particularly in the presence of ischemia, perforation, or underlying stenosis [12, 66]. Manual propulsion of gallstones through the ileocecal valve should be reserved for highly selected situations due to the danger of mucosal injury and intestinal perforation [12, 20, 24, 27, 28, 66]. Likewise, attempts to crush gallstones in situ can damage the intestinal wall and should be avoided [20, 27, 66, 69]. Multiple gallstones can generally be extracted through a single incision freeing the intestines and moving smaller gallstones to larger ones. In case of sigmoid obstruction, resection that removes gallstones and underlying stenosis has been recommended [12].
\nThe main long-standing controversy in biliary ileum management is whether surgery should be performed simultaneously with relief of bowel obstruction (one-stage procedure) or later (two-stage procedure).
\nIn 1922, Pybus successfully extracted a limestone blocking the ileum, closed the duodenal fistula, and drained the gallbladder after removing two additional gallstones from it. In 1929, Holz extracted a limestone at the sigmoid level, and after removing a second limestone in the duodenum, he closed the gallbladder fistula and removed the gallbladder. The author recommended this procedure for patients in satisfactory general conditions. In 1957, Welch successfully performed a one-stage surgery in a patient who was well prepared after recurrent intestinal gallstone obstruction. The authors suggested the feasibility of the operation under optimal conditions. In 1965, Berliner et al. [70] reported three similarly managed and mentioned cases that when the patient is adequately hydrated with restored serum electrolytes, it does not represent an operational risk and a one-stage surgical procedure should be considered. The authors recommend considering the one-step procedure in selected cases. The incidence of recurrence commonly cited is 2–5%, but a recurrence of up to 8% has also been reported after only enterolithotomy; half of these new onset events occurred within 30 days [71]. It should be considered that relapse rates of 17–33% have also been reported [12, 72, 73].
\nThe possibility of recurrent cholecystitis and acute cholangitis [12, 70] in patients with unrepaired gallbladder fistulas or retained gallbladder has been highlighted. Acute cholangitis has been reported in 11% of patients with cholecystoduodenal fistula and in 60% with gallbladder colic fistula [12, 52, 53, 67, 68]. With a one-stage procedure, further events related to gallstones are avoided [18].
\nA potential long-term complication of biliary enteric fistula could be gallbladder cancer. Bossart et al. [74] found an incidence of 15% of gallbladder carcinoma in 57 patients undergoing surgery for these fistulas, compared with 0.8% among all patients with cholecystectomy.
\nOn the other hand, simple enterolithotomy has long been associated with lower mortality [13]. It should be taken into account that the severity of each case affects the outcome of a particular surgical procedure and that mortality is not an absolute consequence of the surgical procedure itself. In the Clavien et al.’s [12] report, when patients were comparable in terms of age, concomitant disease, and APACHE II score, operational mortality and morbidity rates were not significantly different.
\nIn 2003, Doko et al. [75] reported a series of 30 patients with morbidity of 27.3% in patients undergoing enterolithotomy alone and 61.1% for a one-stage procedure. Mortality was 9% after enterolithotomy and 10.5% after a one-stage procedure. The American Society of Anesthesiologists (ASA) scores were similar between the two groups, but operating times were significantly longer for the one-step procedure. Urgent fistula repair was significantly associated with postoperative complications. The authors concluded that enterolithotomy is the procedure of choice, with a one-stage procedure reserved for patients with acute cholecystitis, gallbladder gangrene, or residual gallstones [12].
\nIn 2008, Riaz et al. [76] reported their retrospective experience with 10 patients diagnosed with bileous ileus. The choice of surgical procedure was largely determined by the patient’s clinical condition. Five patients underwent enterolithotomy only (group 1), while the remaining five patients underwent cholecystectomy and fistula repair (group 2). In group 1, all patients were hypertensive and diabetic. All patients were hemodynamically unstable, with metabolic acidosis and prerenal azotemia. The ASA score was III or higher in all patients. In group 2, only two patients were hypertensive and all were hemodynamically stable at presentation with an ASA score of II. There was no operational mortality in both groups.
\nMany patients with biliary ileus are elderly, with comorbidities, in poor general conditions and have a delayed diagnosis, which leads to dehydration, shock, sepsis, or peritonitis. Relief of gastrointestinal obstruction with simple enterolithotomy is the safest procedure for these patients [19, 21].
\nAt laparotomy, examination and careful palpation of the entire intestine, gallbladder, and extrahepatic bile duct is recommended in order to rule out gallstones, bile loss, abscesses, or necrosis [1, 2, 9, 14, 18, 77]. Cholecystectomy and fistula repair reduce the need for reoperation and the incidence of complications related to the persistence of the fistula, including recurrent ileus, cholecystitis, or cholangitis, but are justified only in selected patients who are adequately stabilized in good general condition, with good reserve cardiorespiratory and metabolic, and are able to withstand a more prolonged operation, unless it has been clearly demonstrated that gallstones do not remain in the gallbladder [10, 12, 21, 67, 78, 79].
\nAccording to several authors, enterolytictomy alone is the best option for most patients with biliary ileus. The one-step procedure should only be offered to highly selected patients with absolute indications for biliary surgery at the time of presentation and who have been adequately reanimated [6, 7, 13, 21, 29, 31, 52, 53, 67].
\nThe demonstration of gallstones, the appearance of symptoms, or a persistent cholecystointeric fistula indicates the need for cholecystectomy, closure of the fistula, and exploration of the common duct [18]. It has been pointed out that delayed cholecystectomy as a second procedure is clearly justified only in cases of persistence of symptoms [13, 21]. Cholecystectomy and fistula closure are recommended 4–6 weeks later [7, 13, 29, 80]. A 2.94% mortality rate has been reported in this group of patients [25].
\nThe most common postoperative complication was wound infection. In 1961, Raiford [5] observed an overall wound infection rate of 75%. Localized peritonitis, respiratory complications, phlebitis, and recurrent obstruction due to residual gallstones and cholangitis have also been observed. Wound infection continues to be the most common complication, with rates of 27 and 42.5%, as reported by Clavien et al. [12] and Rodríguez Hermosa et al. [19], respectively. Several authors have reported no significant differences in postoperative complications between patients treated with enterolithotomy or enterolithotomy, cholecystectomy, and closure of fistulas [12, 21, 67, 80]. The least common complications were wound dehiscence, cardiopulmonary and vascular complications, sepsis, intestinal and biliary fistulas, and urinary tract infections [12, 21, 80].
\nBiliary ileum is predominantly a geriatric disease and as many as 80–90% of patients have concomitant medical diseases. Hypertension, diabetes, congestive heart failure, chronic lung disease, and anemia are the most common comorbidities [25]. These associated conditions must be taken into consideration, as they can influence the results of the treatment [1].
\nMortality rates were reported up to 44% in the late 1800s, while in the first half of the twentieth century, these rates remained between 40 and 50% [14, 22]. In the 1990s, significant reductions in mortality were observed at 15–18%, at current rates of less than 7% [13, 25]. In particular, simple enterolithotomy has long been associated with a mortality of 11.7% compared to 16.9% for the one-stage procedure (enterolithotomy plus cholecystectomy and fistula closure) [13]. As described by Kirchmayr et al. [79], four main reasons could be responsible for the high number of lethal courses. First of all, the biliary ileum is a disease of the elderly. Second, concomitant diseases such as cardiorespiratory diseases and/or diabetes mellitus are frequent. Third, due to uncommon symptoms, the diagnosis is difficult and an average delay of 4 days from the start of symptoms to hospitalization is reported. Fourth, postoperative recovery is also hampered; age-related complications such as pneumonia or heart failure are more frequent than complications associated with surgery.
\nThe authors noted that fistula closure, performed during the initial procedure, was independently associated with a higher mortality rate than enterolithotomy alone. When intestinal resection was indicated, it was also associated with a higher mortality rate than with enterolithotomy alone. However, if you consider the fact that intestinal resection is not exactly an option but a requirement due to the conditions of the intestinal segment, the mortality for those patients who underwent enterolithotomy alone or intestinal resection is actually 6.53%.
\nBiliary ileum or gastrointestinal obstruction from gallstones accounts for less than 1% of cases of gastrointestinal obstruction, with a higher frequency among the elderly. Computed tomography has proven to be the most accurate diagnostic modality, but validation of diagnostic criteria is required. Surgical relief of the obstruction is the cornerstone of the treatment. Given the high incidence of comorbidity in these patients, a good judgment is needed in the choice of the surgical procedure. Enterolithotomy remains the mainstay of surgical treatment. A one-stage cholecystectomy and fistula repair are justified only in selected patients in good general condition and adequately stabilized preoperatively. Two-stage surgery is an option for patients with persistent symptoms after an enterolithotomy. Extensive prospective studies of laparoscopic and endoscopic guided procedures are planned.
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