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Pathophysiology of Pancreatitis

Discuss about the Disease Pathophysiology and Ultrasound.

Medical imaging involves the use of various technologies for monitoring, diagnosis and treatment of medical conditions. There are different types of medical imaging techniques like the computed tomography (CT), medical resonance imaging, ultrasound, X-ray, positron emission tomography (PET), PET-CT, among others. The features of a medical condition like a tumor mass or cyst can be visualized using these techniques. X-ray imaging was the first diagnostic tool to be discovered followed by the invention of ultrasound imaging (Haidekker 2013).

This report focuses on the use of ultrasound technology for the detection of various medical conditions like pancreatitis, endometriomas and epididymitis. Ultrasound imaging makes use of the properties of high frequency sound waves to image abnormalities in organs during a diseased condition. Ultrasound has frequency ranging between 20 Hz to 20 kHz. This technology involves the use of sound waves which travel through the body and are reflected at the tissue interfaces. The time taken for the waves to return determines the depth of the surface. The ultrasound waves travel from the transducer to the different tissues or organs and then gets reflected back to the transducer as echoes. The transducer converts these echoes to electrical impulses which are finally transformed into a computerized ultrasound image. It has a low instrumentation cost and it is easy to use which essentially adds to its popularity in diagnosis of critical medical conditions (Wilhjelm et al. 2013).

This report focuses on 3 different cases of medical conditions, their pathophysiology and their surface appearances in ultrasound imaging. The 3 different medical conditions described in this study are Pancreatitis, Endometriomas/Endometriosis and Epididymitis. These diseases are caused by various environmental factors as well as bacterial infections. Part A of each medical condition describes its pathophysiology while part B describes the sonographic appearances associated with the disease.

Pancreatitis can be divided into acute and chronic Pancreatitis. Acute Pancreatitis (AP) is characterized by the presence of necrotic areas, interstitial edema, pancreatic tissue hemorrhage and fluid collections. Chronic Pancreatitis (CP) is characterized by the presence of ductal calcifications, dilations, obstructions, pseudocysts and lesions (Sankaran et al. 2015).

AP involves the loss of compartmentalization both at the intracellular and extracellular levels. Obstruction of the outflow of bile salts and their subsequent toxic effects leads to destruction of the pancreatic ducts. Alcohol consumption causes disruption of the plasma membrane functions, balance between protease inhibitors and proteolytic enzymes, resulting in cell destruction, enzyme activation and autodigestion (Sah, Garg and Saluja 2012). Interstitial edema and inflammation are the major features of pancreatitis. Further progression of the disease is characterized by the polymorphonuclear granulocyte accumulation in pancreatic areas and release of enzymes from leukocytes. Various risk factors lead to the development of CP. These include various environmental factors like nicotine and alcohol consumption, nutritional factors, among others (Yadav and Lowenfels 2013). Other factors include hereditary mutations, autoimmune factors and obstruction of ducts. CP involves fibrosis of the glandular tissue. The secretory parenchymal cells undergo various processes like apoptosis or necrosis, duct obstruction and inflammation. Pancreatic stellate cells (PSCs) are responsible for fibrosis, which results in extracellular matrix (ECM) formation in the various interstitial spaces (Apte et al. 2013). ECM formation also occurs in the spaces that lack acinar cells or consist of injured duct cells. The various morphological changes associated with CP involve loss of lobular morphology and structure of pancreas. It also involves malformation of large ducts, abnormalities in the composition and arrangement of the islets. These are irreversible processes and the abnormal morphological changes leads to impairment of the endocrine and exocrine functions. This ultimately results in malnutrition and even diabetes.

Sonographic Appearances of Pancreatitis

Pancreatitis arises due to injury to the duct or acinar cells and cells of the interstitial mesenchyma. Following injury, the activation step involves expression of α smooth muscle actins, proliferation and secretion of fibrillar collagens by the PSCs. Injury to various tissues or cells of the pancreas lead to cellular apotosis or necrosis and cytokine release from macrophages or already existing mesenchymal cells. The damaged pancreatic cells undergo phagocytosis by the macrophages resulting in cytokine release, subsequently resulting in activation and eventual proliferation of PCSs surrounding the injury site. This results in transformation of PCSs to myofibroblasts.

However, another alternative hypothesis describes a direct role of the etiological factor in Pancreatitis development. The factors like alcohol, nicotine directly activates the existing fibroblast cells. Subsequently myofibroblasts are produced and the ECM replaces the alcohol or nicotine infiltrates. This results in architectural and functional damage to the pancreatic cells. It involves enhanced production of matrix metalloproteinases (MMP) 3 and 9 by the myofibroblasts. These metalloproteinases are regulated by the tumor growth factor cytokines resulting in increased pancreatic fibrogenesis. Apart from alcohol and nicotine consumption, hereditary factors also play an important role in the development of Pancreatitis. Mutation in the SPINK1 gene, which encodes the pancreatic secretory trypsin inhibitor also results in the development of hereditary CP (Brock et al. 2013).

The various diagnostic techniques provided by ultrasonography include the grayscale B mode, Doppler imaging and tissue harmonic imaging. Grayscale B mode helps to determine the pancreatic structure, size, volume, border, echogenicity, surrounding regions and ducts. Doppler imaging helps to determine the outline of the pancreas, and the structure of the surrounding vessels. Small calcifications present in the pancreas, which are characteristics of CP, is visualized as twinkling artifacts using Doppler imaging technique. It can also help to distinguish between necrosis (without blood supply) and inflammation (with blood supply) associated with Pancreatitis. Tissue harmonic imaging helps to distinguish between solid and liquid necrotic masses (Dimcevski et al. 2013).

Ultrasound generally determines the severe changes in pancreatic structure and size in AP. A typical horseshoe shape, homogenous and echogenic structure constitutes the sonographic appearances of a normal pancreas. The diameter of a normal pancreas does not exceed 20-22mm. A normal pancreas is also characterized by the absence of fluid structures, fluid collections and lymph node like structures. AP is associated by the volume increase, changes in the structure of the parenchyma and loss or significant decrease of echogenicity. Increased size of the pancreas results in significant displacement of the organs in the abdomen like the stomach and the colon, among others. A diameter of greater than 24mm is generally a sign of Pancreatitis. Other sonographic appearances involve the appearance of a bulge in the anterior position of the abdominal wall, necrotic or oedemic areas (due to non-homogenicity of the pancreas). There are 2 types of oedema: incipient and massive. In incipient oedema, echogenicity is normal while the pancreas is hypoechogenic in massive oedema.

Endometriosis and its Pathophysiology

Accumulation of fluid in acute necrotic Pancreatitis is visualized by endoscopic ultrasound. The fluid accumulations occurring during AP can be classified into Walled off pancreatic necrosis (WOPN) and acute pseudocysts. WOPN occurs four weeks after the development of AP and consists of masses of encapsulated necrotic materials with fluid accumulations. Acute pseudocysts arise during interstitial pancreatitis characterized by the presence of oedema. Acute pseudocysts contain negligible amounts of solid necrotic materials and consist primarily of fluid contents (Ramia et al. 2012).

Endometriosis is a proinflammatory disease, chronic and dependant on the estrogen hormone. It affects women who have reached their reproductive age. It is a gynecological condition involved in aberrant growth of endometrium like tissues outside of the uterus. It is generally asymptomatic but symptoms can also arise like dysmennorhea, severe pelvic pain, irregular and severe bleeding, pain during urination and defecation, nausea, vomiting, dyspareunia, fertility reduction, among others (Vercellini et al. 2014). Endometriosis is generally found in the pelvic regions like the ovaries, fallopian tubes, uterus and its associated ligaments, cul-de-sac, as well as in the ureters, rectovaginal septum, bowels, urinary bladders, appendix, among others. The pathophysiology of endometriosis involves endometrial lesion development, increase in estradiol production and progesterone resistance, vasculogenesis, angiogenesis and immune dysfunction (Rocha, Reis and Taylor 2013).


The endometrial lesion development is described by 3 different hypotheses. The Sampson theory proposes the dissemination of endometrial tissue into the peritoneal cavity during menstruation and subsequently is implanted on either the pelvic organs or the peritoneal tissue. The theory of coelomic metaplasia describes that various environmental, hormonal or infectious stimuli induces metaplasia of visceral and abdominal peritoneal cells leading to endometriosis. The theory of embryonic rest describes that estrogen stimulus enables migration of the Mullerian duct during embryonic development. The cells remaining after the migration gives rise to endometrial lesions. The recent stem cell theory is supported by several experimental data. It proposes the participation of endometrial and bone-marrow stem cells in the development of endometriosis (Gargett et al. 2014).

The attachment of the lesion depends on the stromal cells of the endometrium; while the glandular cells are involved in the growth and subsequent spread of the lesion. Women showing overexpression of collagen, fibronectin, laminin of the peritoneal cavity have an increased risk of developing endometriosis. After attachment, the extracellular matrix (ECM) is degraded, enabling invasion of the endometrial cells, development of endometriotic foci leading to lesion progress. Endometriosis is characterized by increased expression of MMPs like MMP-2, 3, 7 and 9 (Shan et al. 2013). Moreover, the expression of the urokinase-type plasminogen activator (uPA) is also found to be increased in endometriosis. After menstruation, endometrium reconstruction is brought about by Estradiol (active form of estrogen). The endometriotic lesions produce estradiol in high amounts, thereby helping in implantation in peritoneal cavity.

Sonographic Appearances of Endometriosis

Angiogenesis involves the development of new blood vessels from pre-existing ones, while vascularization involves the de novo production of blood vessels during embryogenesis. Lesion development in endometriosis depends on the development of new blood vessels for supply of oxygen and nutrients. Increased expression of vascular endothelial growth factor is responsible for angiogenesis during endometriosis. Endometriosis also involves the process of vascularization for establishment of vascular network.

Functional loss or alterations of immune mediators produced by cells of both innate and adaptive immunity are also involved in endometriosis. These cells include macrophages, neutrophils, dendritic cells, natural killer cells, T and B lymphocytes. Cytokines and chemokines like tumor necrosis factor α, Interleukin 6, 8, 10 and monocyte chemoattractant protein 1 are involved in the establishment and subsequent survival of lesions in endometriosis (Ahn et al. 2015).

The endometrium undergoes changes during the menstrual cycle. During the menstrual phase, it appears as thin, bright and echogenic. A trilaminar appearance, outer echogenic layer, middle hypoechoic layer, and inner echogenic layer characterize the proliferative phase. A thick and uniform echogenic layer characterizes the secretory phase. The functional layer appears oedematous, while the basal layer remains isoechoic. In premenopausal women, the endometrium varies in thickness. During menstruation it is 2-4mm, during early proliferative phase it is 5-7mm, in late proliferative phase it is 11mm in thickness while in the secretory phase it is 7-16mm. In post menopausal women the endometrial thickness is generally less than 5mm.

Transvaginal sonography is the standard in diagnosing endometriosis, which involves imaging the ovaries and uterus. However, patients suffering from severe pelvic pain are subjected to sonography of additional regions like the bowel wall, cul-de-sac and the rectovaginal septum. This helps in the detection of rectosigmoid endometriosis (Said and Azzam 2014).

Endometriosis is characterized by the presence of implants, which can be either superficial or deep. Ultrasound is poor in detecting peritoneal implants but can better detect endometriomas. Endometriomas appear as homogenous and focal lesions. They appear unilocular but in some cases may be multilocular with presence of septa. Multiple endometriomas may appear with presence of mural nodules, which are hyperechoic. Color Doppler imaging shows absence of blood flow.


Early diagnosis of endometriosis is a major challenge but women showing possible symptoms should be subjected to imaging techniques. Endometriomas also called chocolate cysts appear on the ovary and constitute the most common feature associated with sonography of patients suffering from endometriosis. Sonographic appearances of endometriosis involve the appearance of solid nodules with poorly defined and blurred borders. Ultrasonographic scan in Endometriosis reveals the presence of a cystic mass with diffused and low echo levels. However, Endometriomas may sometimes appear as a solid or cystic mass (either simple or complex). Endometriomas are visualized as vascularized, rounded, papillary projections having smooth contours with the presence of cyst locules and cyst fluid showing low echogenicity levels.

Epididymitis: Pathophysiology and Sonographic Appearances

Epididymis is a tubular and coiled organ which remains attached with the testis. This organ is associated with the maturation, storage and eventual transport of the sperm (Dacheux and Dacheux 2014). Epididymitis is a very common medical condition and is usually differentiated into the acute and chronic forms. Acute epididymitis (AE) can occur at any age while the chronic form occurs in males within the range of 19-52 years. Mostly men of reproductive age are affected by this disease.

AE is characterized by inflammation, swelling and pain in the epididymis. The epididymis becomes tender and gets swelled in a unilateral direction (Yusuf et al. 2013). From the cauda epididymis, the swelling spreads to the entire epididymis and ultimately reaching testis. The symptoms may range from mild tenderness of the epididymis to severe urosepsis. AE is generally caused by infection of bacterial pathogens. These urinary pathogens move from the urethra and the urinary bladder in a retrograde fashion, ultimately leading to colonization of the epididymis. They move through the vas deferens and ejaculatory ducts, eventually reaching the epididymis. These bacterial pathogens cause inflammation of the epididymis. Initially, the inflammation starts from the epididymis tail, eventually reaching the body and the head. Inflammation of the testis is called epididymo-orchitis. Epididymitis initially starts as urethritis and ultimately attaining the epididymitis form. Chlamydia trachomatis was found to be the principal bacterial pathogen associated with epididymitis in young patients (Malhotra et al. 2013). Patients below 35 years of age are generally associated with sexually transmitted diseases resulting in epididymitis. In this case, the pathogen C. trachomatis plays a very important role. However, in patients belonging to the above 35-year age group, enteric pathogens like Escherichia coli play an important role in the development of the disease. Viral pathogens have also been sometimes associated with the disease.

Chronic epididymitis (CE) is characterized by pain and discomfort in the testicles, scrotum or epididymis. The pain may spread to the groin, thigh and eventually to the lower back portion. There also appear changes in the semen consistency and color. In rare cases, the inflammation spreads to the prostate gland. This causes pain and discomfort in the perineum, groin and thighs leading to improper discharge of urine. Physical examination may reveal either an abnormal or normal looking epididymis. Infection may be responsible but some cases also report non-infectious epididymitis. Inflammatory reactions following an infection are the major cause of CE. Tuberculosis is again one of the principal causes of CE (Kho and Chan 2012). However, in tuberculosis associated epididymitis, thickening of the scrotum and development of fistula are the major features in addition to swelling of epididymis. Use of drugs like Amiodarone has been found to induce epididymitis. Moreover, certain diseases like the Behcet’s disease are also associated with CE. Severe pain during CE may also occur because of vasectomy-induced obstructions. These obstructions cause the urine to flow back into the ejaculatory ducts resulting in chronic pain. Other conditions associated with CE involve urinary tract infections, more than one sexual partners, improper usage of protection measures and depression (Çek, Sturdza and Pilatz 2017).

Ultrasonography is the most essential and non-invasive method for diagnosis of epididymitis. A normal scrotum is characterized by the presence of a pair of testicles. The scrotum appears as a sac consisting of both fibrous and muscular tissues. It consists of a left and right hemiscrotum and both these regions are separated by raphae. The testicle is ovoid and measures approximately 5cm in length, 3cm in height and 2cm in breadth. It is characterized by an intermediate and homogenous echogenicity. The epididymis is comma-shaped, elongated structure having a head, body and tail. The head is isoechoic and sometimes hyperechoic; while the body and tail are isosechoic. The tunica albuginea or the fibrous capsule appears as a thin band outside the testis. It appears as an echogenic band.

Epididymitis is the most common factor responsible for scrotal pain in males. Sonographic appearances during AE involve the presence of a hypervascular and highly enlarged epididymis. It has a heterogenous echotexture, mainly hypoechoic. Color Doppler Ultrasonography is highly sensitive and can detect inflammation resulting from epididymitis. Other features include the presence of pyelocele or hydrocele, thickening of the scrotal wall, calcification and formation of fistula. Abscess formations in the epididymis appear as hypoechoic areas. In Epididymo-orchitis, the testicle appears as a non-homogenous and enlarged structure. Grayscale Ultrasonography and color Doppler imaging of the thickened scrotal walls (scrotal cellulitis) shows hypoechoic areas with increased blood flow. Abscesses on the scrotal wall appear as loculated fluid masses with irregular borders and low level echoes.

Development of hydroceles or fluid masses is the primary reason of scrotal swellings which are painless. Hydroceles are generally anechoic but sometimes internal echoes appear depending on the cholesterol or protein content of the fluid accumulations. Calcifications of the testicles generally appear as small, 2-3mm, multiple, non-shadowing foci which are echogenic. Scrotoliths or mobile scrotal calcifications appear as 10mm echogenic free floating foci outside testicles. Spermatoceles usually arise after vasectomy and appear as multilocular lesions, showing internal echoes (Kuhn et al. 2016).

Conclusion

Medical imaging tools enable proper diagnosis of critical medical conditions. Ultrasonography is a low cost and efficient technique for imaging tissue abnormalities like tumors, cysts, among others. This report describes the pathophysiology of Pancreatitis, Endometriomas and Epididymitis. Pancreatitis is generally associated with alcohol or nicotine consumption. It is an inflammatory disease associated with the destruction of parenchymal cells and deformation of the pancreas. Immunological factors have been described to play a role in the development of endometriomas. It is a proinflammatory disease of the pelvic cavity region. It results in infertility and severe pelvic pain in women. This disease is characterized by the development of tissues resembling those of the endometrium on the uterus, ovary and other regions of the pelvic cavity. Epididymitis is an infection of the epididymis and is specific for males who have reached their reproductive age. Epididymitis is characterized by the inflammation and swelling of the epididymis. It is generally caused by bacterial infections but other factors may also be involved. Sometimes the infection progresses from the epididymis and into the testis. This condition is called epididymo-orchitis. Diagnosis of all the 3 above mentioned medical conditions were carried out by Ultrasonography. These ultrasound waves help in imaging the pancreas, to identify any abnormalities (like tumors and necrotic masses) and determine the size and structure of the diseased pancreas. Transvaginal Ultrasonography is the most important in diagnosis of endometriosis. It shows the presence of cystic masses and nodular structures on the surfaces of ovaries and uterus. Ultrasonography is highly essential for diagnosis of Epididymitis. It reveals the enlargement of the epididymis and other abnormalities like presence of calcifications, thickened scrotal walls and fistula. Therefore, it can be concluded that Ultrasonography plays a very important role in the diagnosis of diseases in a non-invasive and cost effective way.

Reference List

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