appendix

Anatomy

The vermiform appendix is present only in humans, certain anthropoid apes and the wombat (a nocturnal, burrowing Australian marsupial). It isa blind muscular tube with mucosal, submucosal, muscular and serosal layers. Morphologically, it is the undeveloped distal end of the large caecum found in many lower animals. At birth, the appendix is short and broad at its junction with the caecum, but differential growth of the caecum produces the typical tubular structure by about the age of 2 years (Condon). During childhood, continued growth of the caecum commonly rotates the appendix into a retrocaecal but intraperitoneal position (Fig. 1).

Figure 1 : appendix relationship with other organ, cecum, ileum,mesoappendix


In approximately a quarter of cases, rotation of the appendix does not occur resulting in a pelvic, suhcaecal or paracaecal position. Occasionally, the tip of the appendix becomes extraperitoneal lying behind the caecum or ascending colon. Rarely, the caecum does not migrate during development to its normal position in the right lower quadrant of the abdomen. In these circumstances the appendix can be found near the gall bladder or, in the case of situs inversus viscerum, in the left iliac fossa causing diagnostic difficulty if appendicitis develops (Fig. 2, 3).


Figure 2 show type of appendix correlate with tip of appendix




Figure 3 show variation in position of appendix


The position of the base of the appendix is constant, being found at the confluence of the three taeniae coli of the caecum which fuse to form the outer longitudinal muscle coat of the appendix. At operation, use can he made of this to find an elusive appendix, as gentle traction on the taeniae coli, particularly the anterior taenia, will lead the operator to the base of the appendix.
The mesentcry of the appendix or mesoappendix arises from the lower surface of the mesentery of the terminal ileum, and itself is subject to great variation. Sometimes as much as the distal third of the appendix is bereft of mesoappendix. Especially in childhood, the mesoappendix is so transparent that the contained blood vessels can he seen (Fig. 4).


Figure 4 show artery supply appendix, appendiceal artery, branch of ileocolic artery.



In many adults it becomes laden with fat, which obscures these vessels. The appendicular artery, a branch of the lower division of the ileocolic artery, passes behind the terminal ileum to enter the mesoappendix a short distance from the base of the appendix. It then comes to lie in the free border of the mesoappendix. An accessory appendicular artery may be present but, in most people, the appendicular artery is an ‘end-artery’, thrombosis of which results in necrosis of the appendix (syn. gangrenous appendicitis). Four, six or more lymphatic channels traverse the mesoappendix to empty into the ileocaecal lymph nodes.

Microscopic anatomy

The appendix varies considerably in length and circumference. The average length is between 7.5 and 10 cm. The lumen is irregular, being encroached upon by multiple longitudinal folds of mucous membrane lined by columnar cell intestinal mucosa of colonic type (Fig. 5).

Figure 5 show microscopic anatomy of appendix.

Crypts are present but are not numerous. In the base of the crypts lie argentaffln cells (Kultschitzsky cells) which may give rise to carcmnoid tumours (vide in Ira). The appendix is the most frequent site for carcinoid tumours which may present with appendicitis due to occlusion of the appendiceal lumen.
The submucosa contains numerous lymphatic aggregations or follicles. This profusion of lymph tissue has promoted the concept that the appendix is the human equivalent of the avian bursa of Fabricius as a site of maturation of thymus-independent lymphocytes. While no discernible change in immune function results from appendicectomy, the prominence of lymphatic tissue in the appendix of young adults seems important in the aetiology of appendicitis (vide infra).

Acute appendicitis

While there are isolated reports of perityphlitis (fatal inflammation of the caecal region) from the late 1500s, recognition of acute appendicitis as a clinical entity is attributed to Reginald Fitz who presented a paper to the first meeting of the Association of American Physicians in 1886 entitled ‘Perforating inflammation of the vermiform appendix’. Soon afterwards Charles McBurney described the clinical manifestations of acute appendicitis including the point of maximum tenderness in the right iliac fossa that since bears his name. The incidence of appendicitis seems to have risen greatly in the first half of the twentieth century, particularly in Europe, America and Australasia, with up to 16 per cent of the population undergoing appendicectomy. In the past 30 years the incidence has fallen dramatically in these countries, with the number of operations in England and Wales declining from 113 000 in 1966 to 48 000 in 1990. In developing countries, which are adopting a more refined Western-type diet, the incidence continues to rise. No reason has been established for these changes in the incidence of acute appendicitis.
Acute appendicitis is relatively rare in infants, and becomes increasingly common in childhood and early adult life, reaching a peak incidence in the teens and early 20s. After middle age the risk of developing appendicitis in the future is quite small. The incidence of appendicitis is equal amongst males and females before puberty. In teenagers and young adults the male:female ratio increases to 3:2 at the age of 25 years, thereafter the greater incidence in males declines.

Aetiology

There is no unifying hypothesis regarding the aetiology of acute appendicitis. While appendicitis is clearly associated with bacterial proliferation within the appendix, no single organism is responsible, indeed a mixed growth of aerobic and anaerobic organisms is usual. The initiating event causing bacterial proliferation is controversial. Obstruction of the appendix lumen has been widely held to be important, and indeed some form of luminal obstruction by either a faecolith or stricture is found in the majority of cases. A faecolith is composed of inspissated faecal material, calcium phosphates, bacteria and epithelial debris. Rarely a foreign body is incorporated into the mass. The incidental finding of a faecolith is a relative indication for prophylactic appendicectomy.

A fibrotic stricture of the appendix usually indicates previous appendicitis which resolved without surgical intervention. Obstruction of the appendiceal orifice by tumour, particularly carcinoma of the caecum, is an occasional cause of acute appendicitis in middle age and the elderly. Intestinal parasites, particularly Oxyuris vermicularis (syn. pinworm), can proliferate in the appendix and occlude the lumen.



Pathology

Obstruction of the appendiceal lumen seems to be essential for development of appendiceal gangrene and perforation. Yet, in many cases of early appendicitis the appendix lumen is patent despite the presence of mucosal inflammation and lymphoid hyperplasia. Occasional clustering of cases amongst children and young adults suggests an infective agent, possibly viral, which initiates an inflammatory response, which within the narrow lumen of the appendix leads to luminal obstruction. Once obstruction occurs, continued mucus secretion and inflammatory exudation increase intraluminal pressure, obstructing lymphatic drainage. Oedema and mucosal ulceration develop with bacterial translocation to the submucosa. Resolution may occur at this point either spontaneously or in response to antibiotic therapy. Where the condition progresses, further distension of the appendix may cause venous obstruction and ischaemia of the appendix wall. With ischaemia, bacterial invasion occurs through the muscularis propria and submucosa producing acute appendicitis.

Finally, ischaemic necrosis of the appendix wall produces gangrenous appendicitis, with free bacterial contamination of the peritoneal cavity. Alternatively, the greater omentum and loops of small bowel become adherent to the inflamed appendix, walling off the spread of peritoneal contamination resulting in a phlegmonous mass or paracaecal abscess. Rarely, appendiceal inflammation resolves leaving a distended mucus-filled organ termed a mucocele of the appendix.


It is the potential for peritonitis that is the great threat of acute appendicitis. Peritonitis occurs as a result of free migration of bacteria through an ischaemic appendicular wall, through frank perforation of a gangrenous appendix or delayed perforation of an appendix abscess. Factors which promote this process include extremes of age, immunosuppression, diabetes mellitus, faecolith obstruction of the appendix lumen, a free-lying pelvic appendix and previous abdominal surgery which limits the ability of the greater omentum to wall off the spread of peritoneal contamination.


In these situations a rapidly deteriorating clinical course is accompanied by signs of diffuse peritonitis and systemic sepsis syndrome.

Clinical diagnosis — history

The classical features of acute appendicitis begin with poorly localised colicky abdominal pain.
This is due to midgut visceral discomfort in response to appendiceal inflammation and obstruction. The pain is frequently first noticed in the periumbilical region and is similar to, but less intense than, the colic of small bowel obstruction. Central abdominal pain is associated with anorexia, nausea and usually one or two episodes of vomiting which follow the onset of pain (Murphy). Anorexia is a useful and constant clinical feature, particularly in children. The patient often gives a history of similar discomfort which settled spontaneously.
With progressive inflammation of the appendix, the parietal peritoneum in the right iliac fossa becomes irritated producing more intense, constant and localised somatic pain which begins to predominate. This is often reported by the patient as an abdominal pain which has shifted and changed in character. Typically, coughing or sudden movement exacerbates the right iliac fossa pain.
The classical visceral—somatic sequence of pain is present in only about half those patients subsequently proven to have acute appendicitis. Atypical presentations include pain which is predominantly somatic or visceral and poorly localised. Atypical pain is more common in the elderly in whom localisation to the right iliac fossa is unusual. An inflamed appendix in the pelvis may never produce somatic pain involving the anterior abdominal wall, but may instead cause suprapubic discomfort and tenesmus. In this circumstance, tenderness may only be elicited on rectal examination and is the basis for the recommendation that a rectal examination should be performed on every case of lower abdominal pain.
During the first 6 hours there is rarely any alteration in temperature or pulse rate. After that time, slight pyrexia (37.2—37.70C) with corresponding increase in the pulse rate to 80 or 90 is usual. However, in 20 per cent of cases there is no pyrexia or tachycardia in the early stages. In children a temperature greater than 38.50C suggests other causes, for example mesenteric adenitis (vide in Ira).
Typically, two clinical syndromes of acute appendicitis can be discerned, acute catarrhal (nonobstructive) appendicitis and acute obstructive appendicitis. The latter is characterised by a much more acute course. The onset of symptoms is abrupt and there may be generalised abdominal pain from the start. The temperature may be normal and vomiting is common, so that the clinical picture may mimic acute intestinal obstruction. Once recognised, urgent surgical intervention is required because of the more rapid progression to perforation.




Clinical diagnosis — signs


The diagnosis of appendicitis rests more on thorough clinical examination of the abdomen than on any aspect of the history or laboratory investigation. The cardinal features are those of an unwell patient with low grade pyrexia, localised abdominal tenderness, muscle guarding and rebound tenderness. Inspection of the abdomen may show limitation of respiratory movement in the lower abdomen. The patient is then asked to point to where the pain began and to where it moved (the pointing sign). Gentle superficial palpation of the abdomen, beginning in the left iliac fossa moving anticlockwise to the right iliac fossa, will detect muscle guarding over the point of maximum tenderness, classically McBurney point. Asking the patient to cough or gentle percussion over the site of maximum tenderness will elicit rebound tenderness.
Deep palpation of the left iliac fossa may cause pain in the right iliac fossa (Rovsing’s sign), which is helpful in supporting a clinical diagnosis of appendicitis. Occasionally an inflamed appendix lies on the psoas muscle and the patient, often a young adult, will lie with the right hip flexed for pain relief (the psoas sign). Spasm of the obturator internus is sometimes demonstrable when the hip is flexed and internally rotated. If an inflamed appendix is in contact with the obturator internus, this manoeuvre will cause pain in the hypogastrium (the obturator test) (Zachary Cope). Cutaneous hyperaesthesia may be demonstrable in the right iliac fossa, hut is rarely of diagnostic value.












Special features, according to position of the appendix

Retrocaecal


Rigidity is often absent and even on deep pressure tenderness may he lacking (silent appendix), the reason being that the caecum, distended with gas, prevents the pressure exerted by the hand from reaching the inflamed structure. However, deep tenderness is often present in the loin, and rigidity of the quadratus lumborum may he in evidence. Psoas spasm, due to the inflamed appendix being in contact with that muscle, may he sufficient to cause flexion of the hip joint. Hyperextension of the hip joint may induce abdominal pain when the degree of psoas spasm is insufficient to cause flexion of the hip.

Pelvic

Occasionally early diarrhoea results from an inflamed appendix being in contact with the rectum. When the appendix lies entirely within the pelvis there is usually complete absence of abdominal rigidity, and often tenderness over McBurney’s point is lacking as well. In some instances deep tenderness can he made out just above and to the right of the symphysis pubis. In either event, a rectal examination reveals tenderness in the rectovesical pouch or the pouch of Douglas, especially on the right side. Spasm of the psoas and obturator internus muscles may he present when the appendix is in this position. An inflamed appendix in contact with the bladder may cause frequency of micturition.

Post ileal

Although this is rare, it accounts for some of the cases of missed appendix’. Here the inflamed appendix lies behind the terminal ileum. It presents the greatest difficulty in diagnosis because the pain may not shift, diarrhoea is a feature and marked retching may occur. Tenderness, if any, is ill-defined, although it may he present immediately to the right of the umbilicus.

Special features, according to age

Infants

Appendicitis is relatively rare in infants under 36 months of age and for obvious reasons the patient is unable to give a history. Because of this, diagnosis is often delayed and thus the incidence of perforation and postoperative morbidity is considerably higher than in older children. Diffuse peritonitis can develop rapidly due to the underdeveloped greater omentum, which is unable to give much assistance in localising the infection.

Children

It is rare to find a child with appendicitis who has not vomited. Children with appendicitis usually have complete aversion to food. In addition, they do not sleep during the attack and very often bowel sounds are completely absent in the early stages.

The elderly

Gangrene and perforation occur much more frequently in elderly patients. Elderly patients with lax abdominal walls or obesity may harbour a gangrenous appendix with little evidence of it, and the clinical picture may simulate subacute intestinal obstruction. These features coupled with coincident medical conditions produce a much higher mortality for acute appendicitis in the elderly.

The obese

Obesity can obscure and diminish all the local signs of acute appendicitis. Delay in diagnosis coupled with the technical difficulty of operating in the obese make it wiser to consider operating through a midline abdominal incision

Pregnancy

Appendicitis is the most common extra uterine acute abdominal condition in pregnancy with a frequency of from one in 1500 to one in 2000 pregnancies. Diagnosis is complicated by delay in presentation; early nonspecific symptoms are often attributed to the pregnancy, and the changing location of the appendix during pregnancy. As pregnancy develops during the second and third trimesters, the caecum and appendix are progressively pushed to the right upper quadrant of the abdomen. This displacement can result in flank or back pain, and may be confused with pyelonephritis, while lower abdominal pain may be confused with torsion of an ovarian cyst. Foetal loss occurs in 3—5 per cent of cases, increasing to 20 per cent if perforation is found at operation.

Differential diagnosis

Although acute appendicitis is the most common abdominal surgical emergency, the diagnosis at times can be extremely difficult. It is important to remember that many conditions which mimic appendicitis also require surgical intervention, or if they do not are rarely made worse by appendicectomy. However, there is a number of common conditions that it is wise to consider carefully and, where possible, exclude. The differential diagnosis differs in patients of different ages and in adult life, females have the added differential of diseases of the female genital tract (Table 59.5).

Children

The diseases most commonly mistaken for acute appendicitis are acute gastroenteritis and mesenteric lymphadenitis. In acute gastroenteritis there is intestinal colic together with diarrhoea and vomiting, but localised tenderness does not usually occur. There is often a history of other family members being affected. Post ileal appendicitis may mimic this condition, thus hospital admission and careful observation are warranted. Where serious doubt persists laparoscopy or surgical exploration may be indicated. In mesenteric lymphadenitis, the pain is colicky in nature and the patient may be completely free from pain between attacks, which last for a few minutes. Cervical lymph nodes may be enlarged. If present, shifting tenderness when the child turns on to his or her left side is convincing evidence. The condition presents a common diagnostic difficulty in children and if doubt exists exploration is advisable.
It may be impossible clinically to distinguish Meckel’s diverticulitis from acute appendicitis. The pain is similar, however signs may be central or left-sided. Occasionally, there is a history of antecedent abdominal pain or anaemia.
It is important to distinguish between acute appendicitis and intussusception.Appendicitis is uncommon before the age of 2 years, whereas the median age for intussusception is 18 months. A mass may be palpable in the right lower quadrant and the preferred treatment of intussusception is reduction by careful barium enema.

Henoch—Schönlein purpura

This is often preceded by a sore throat or respiratory infec­tion. Abdominal pain can be severe and be confused with intussusception or appendicitis. There is nearly always an ecchymotic rash, typically affecting the extensor surfaces of the limbs and on the buttocks. The face is usually spared. The platelet count and bleeding time are within normal limits.

Lobar pneumonia and pleurisy

Lobar pneumonia and pleurisy, especially at the right base, may give rise to right-sided abdominal pain and mimic appendicitis. Abdominal tenderness is minimal, pyrexia is marked and chest examination may reveal a pleural friction rub or altered breath sounds on auscultation. A chest radiograph is diagnostic.

Adults

Terminal ileitis


In its acute form terminal ileitis may be indistinguishable from acute appendicitis unless a doughy mass of inflamed ileum can be felt. An antecedent history of abdominal cramping, weight loss and diarrhoea suggests regional ileitis rather than appen­dicitis. The ileitis may be nonspecific, due to Crohn’s disease or Yersiniainfection. Yersinia enterocolitica causes inflammation of the terminal ileum, appendix and caecum with mesenteric adenopathy. If suspected, serum antibody titres are diagnostic and treatment with intravenous tetracycline antibiotic is appropriate. If Yersiniainfection is suspected at operation, a mesenteric lymph node should be excised, divided, and half submitted for microbiological culture (including tuberculosis) and half for histological examination.

Ureteric colic

Ureteric colic does not commonly cause diagnostic difficulty as the character and radiation of pain differ from those of appendicitis. Urinalysis should always be performed and the presence of red cells should prompt a supine abdominal X-ray. Renal ultrasound or an intravenous urogram is diagnostic.

Right-sided acute pyelonephritis

This is accompanied and often preceded by increased frequency of micturition. It may cause difficulty in diagnosis, especially in women. The leading features are tenderness confined to the loin, fever (temperature 390C), and possibly rigors and pyuria.

Perforated peptic ulcer

(Duodenal contents pass along the paracolic gutter to the right iliac fossa.) There is usually a history of dyspepsia and a very sudden onset of pain, which starts in the epigastrium and passes down the right paracolic gutter. In appendicitis the pain starts classically in the umbilical region. Rigidity and tenderness in the right iliac fossa are present in both conditions, but in perforated duodenal ulcer the rigidity is usually greater in the right hypochondrium. Radiography may show gas under the diaphragm. continuesunabated until operation. Usually there is a history of a missed menstrual period and urinary pregnancy test may be positive. Severe pain is felt when the cervix is moved on vaginal examination. Signs of intraperitoneal bleeding usual­ly become apparent and the patient should be questioned specifically regarding referred pain in the shoulder. Pelvic ultrasonography should be carried out in all cases where an ectopic pregnancy is a possible diagnosis.

Testicular torsion

Testicular torsion in a teenager or young adult male is easily missed. Pain can be referred to the right iliac fossa, and shyness on the part of patient may lead the unwary to suspect appendicitis unless the scrotum is examined in all cases.

Acute pancreatitis

Acute pancreatitis should be considered in the differential diagnosis of all adults suspected of acute appendicitis and when appropriate excluded by serum or urinary amylase measurement.

Rectus sheath haematoma

This is a relatively rare but easily missed differential diagnosis. It usually presents with acute pain and localised tenderness in the right iliac fossa, often after an episode of strenuous physical exercise. Localised pain without gastrointestinal upset is the rule. Occasionally, in an elderly patient, particularly those on anticoagulant therapy, a rectus sheath haematoma may present with a mass and tenderness in the right iliac fossa following minor trauma.

Adult females

It is in women of child-bearing age that pelvic disease most often mimics acute appendicitis. A careful gynaecological history should be taken in all women with suspected appen­dicitis concentrating on menstrual cycle, vaginal discharge and possible pregnancy. The most common diagnostic mim­ics are salpingitis, mittelschmerz, torsion or haemorrhage of an ovarian cyst and ectopic pregnancy.

Salpingitis

This is the condition which poses greatest diagnostic diffi­culty in young women. Typically, the pain is lower than in appendicitis and is bilateral. A history of vaginal discharge, dysmenorrhoea and burning pain on micturition are all help­ful differential diagnostic points. There may be a history of contact with sexually transmitted disease. When suspected, the opinion of a gynaecologist should be obtained, and high vaginal swab taken for Chlamydia culture. When serious diagnostic uncertainty persists, diagnostic laparoscopy should be undertaken.

Mittelschmerz

Midcycle rupture of a follicular cyst with bleeding produces lower abdominal and pelvic pain, typically midcycle. Sys­temic upset is rare, pregnancy test is negative and symptoms usually subside within hours. Occasionally, diagnostic laparo­scopy is required.

Torsion/haemorrhage of an ovarian cyst

This can prove a difficult differential diagnosis. When suspected, pelvic ultrasound and a gynaecological opinion should be sought. If encountered at operation, ovarian cystectomy should be performed, if necessary, in women of child-bearing years. Documented visualisation of the contralateral ovary is an essential medicolegal precaution.

Ectopic pregnancy

It is unlikely that a ruptured ectopic pregnancy, with its well-defined signs of haemoperitoneum, will be mistaken for acute appendicitis, but the same cannot be said for a right-sided tubal abortion, or still more for a right-sided unruptured tubal pregnancy. In the latter, the signs are very similar to those of acute appendicitis, except that the pain commences on the right side and stays there. The pain is severe and

Elderly

Sigmoid diverticulitis


In some patients with a long sigmoid loop, the colon lies to the right of the midline and it may be impossible to differentiate between diverticulitis and appendicitis. A trial of conservative management with intravenous fluids and antibiotics is often appropriate, with a low threshold for exploratory laparotomy in the face of deterioration or lack of clinical response.

Intestinal obstruction

The diagnosis of intestinal obstruction is usually clear, the subtlety lies in recognising acute appendicitis as the occa­sional cause in the elderly. As with diverticulitis, intravenous fluids, antibiotics and nasogastric decompression should be instigated with early resort to laparotomy.

Carcinoma of the caecum

When obstructed or locally perforated, carcinoma of the caecum may mimic or cause obstructive appendicitis in adults. A history of antecedent discomfort, altered bowel habit or unexplained anaemia should raise suspicion. A mass may be palpable (vide infra) and barium enema or colonoscopy is diagnostic.

Rare differential diagnoses

Preherpetic pain of the right 10th and 11th dorsal nerves is localised over the same area as that of appendicitis. It does not shift and is associated with marked hyperaesthesia. There is no intestinal upset or rigidity. The herpetic eruption may be delayed for 3—8 hours. Tabetic crises are now rare. Severe abdominal pain and vomiting usher in the crisis. Other signs of tabes confirm the diagnosis. Spinal conditions are sometimes associated with acute abdominal pain, especially in children and the elderly. These may include tuberculosis of the spine, metastatic carcinoma, osteoporotic vertebral collapse and multiple myeloma. The pain is due to compression of nerve roots and may be aggravated by movement. There is rigidity of the lumbar spine and intestinal symptoms are absent. The abdominal crises of porphyria and diabetes mellitus need to he remembered. A urinalysis should be tested in every abdominal emergency. In cyclical vomiting of infants or young children there is a history of previous similar attacks, and abdominal rigidity is absent. Acetone is found in the urine but is not diagnostic as it may accompany starvation. Typhlitisor leukaemic ileocaecal syndrome is a rare hut potentially fatal enterocolitis occurring in immunosuppressed patients. Gram-negative or clostridial(especially C. septicum) septicaemia can be rapidly progressive. Treatment is with appropriate antibiotics and haematopoetic factors. Surgical intervention is rarely indicated.

Investigation

The diagnosis of acute appendicitis is essentially clinical. A full blood count and urinalysis should be performed in all cases. In women of reproductive years, it is wise to obtain a urinary pregnancy test before proceeding to exploration. Pelvic ultrasound is of value in excluding tubal or ovarian disease if suspected. Abdominal ultrasound examination is a useful diagnostic tool, particularly in children, with a diagnostic accuracy of appendicitis in excess of 90 per cent

In dehydrated or elderly patients or where comorbid conditions dictate, serum urea and electrolytes should be checked. If a diagnosis of intestinal obstruction, intussusception or ureteric colic is being entertained, a supine abdominal X-ray should be performed .


Treatment

The treatment of acute appendicitis is appendicectomy. There is a perception that urgent operation is essential to prevent the increased morbidity and mortality of peritonitis. While there should be no unnecessary delay, all patients, particularly those most at risk of serious morbidity, benefit from a short period of intensive preoperative preparation. Intravenous fluids sufficient to establish adequate urine output (catheterisation is needed only in the very ill) and appropriate antibiotics should be given. There is ample evidence that a single perioperative dose of antibiotics reduces the incidence of postoperative wound infection. When peritonitis is suspected, therapeutic intravenous antibiotics to cover Gram-negative bacilli, as well as anaerobic cocci, should be given. Hyperpyrexia in children should be treated with salicylates in addition to antibiotics and intravenous fluids. With appropriate use of intravenous fluids and parentral antibiotics, a policy of deferring appendicectomy after midnight to first case on the following morning does not increase morbidity. However, when acute obstructive appendicitis is recognised, operation should not be deferred longer than it takes to optimise the patient’s condition.

Appendicectomy

Appendicectomy may be performed by conventional open operation or by using laparoscopic techniques. The first surgeon to perform deliberate appendicectomy for acute appendicitis was Lawson Tam, in May 1880. The patient recovered. It is recorded in 1736 that Claudius Amyand successfully removed an acutely inflamed appendix from the hernial sac of a boy.
Appendicectomy should he performed under general anaesthetic with the patient supine on the operating table. When a laparoscopic technique is to be used, a nasogastric tube should be inserted and the bladder must be empty (ensure the patient has voided before leaving the ward). Prior to preparing the entire abdomen with an appropriate antiseptic solution, the right iliac fossa should be palpated for a mass. If a mass is felt, it may, on occasion, be preferable to adopt a conservative approach (vide infra). Draping of the abdomen is in accordance with the planned operative technique, taking account of any requirement to extend the incision or convert a laparoscopic technique to open operation.

Conventional appendicectomy

When the preoperative diagnosis is considered reasonably certain, the incision that is widely used for appendicectomy is the so-called grid-iron incision (a grid-iron was a frame of cross-beams to support a ship during repairs). The grid-iron incision (described first by McArthur) is made at right angles to a line joining the anterior superior iliac spine to the umbilicus, its centre being along the line at McBurney’s point. In the subcutaneous tissues an arterial twig from the superficial circumflex iliac artery usually requires ligation. The external oblique is incised in the line of its fibres along the length of the incision. The fibres of the internal oblique and transversus abdominis are split, and with suitable retrac­tion the peritoneum is opened. If better access is required, it is possible to convert the grid-iron to a Rutherford Morrison incision (vide infra) by cutting the internal oblique and transversus muscles in the line of the incision.
In recent years, a transverse skin crease (Lanz) incision has become more popular, as the exposure is better and extension, when needed, is easier. The incision, appropriate in length to the size and obesity of the patient, is made approxi­mately 2 cm below the umbilicus centred on the midcla­vicular—midinguinal line. The external oblique aponeurosis, internal oblique and transversus muscles are split in the direction of the fibres and the peritoneum is opened. When necessary the incision may be extended medially, with retraction or suitable division of the rectus abdominis muscle.
When the diagnosis is in doubt, particularly in the presence of intestinal obstruction, a lower midline abdominal incision is to be preferred over a right lower paramedian incision. The latter, although widely practised in the past, is difficult to extend, more difficult to close and provides less good access to the pelvis and peritoneal cavity.
Rutherford Morrison’s incision is useful if the appendix
is paracaecal or retrocaecal and fixed. It is essentially an oblique muscle-cutting incision with its lower end over McBurney’s point and extending obliquely upwards and laterally as necessary. All layers are divided in the line of the incision.
Removal of the appendix
It will be assumed that the abdomen has been opened by a skin crease incision. A retractor is placed under the medial side of the wound and the peritoneum, and the abdominal wall is elevated. Serous exudate is removed with a sucker. Pus, if present, is likewise removed having first retained a specimen for microbiological culture. The caecum is identified by the presence of teniae coli, and using a finger or a swab the caecum is withdrawn. A turgid appendix may be felt at the base of the caecum. Inflammatory adhesions must be gently broken with a finger which is then hooked around the appendix to deliver it into the wound. The appendix is conveniently controlled using a Babcock or Lane’s forceps applied in such a way as to encircle the appendix and yet not damage it. The base of the mesoappendix is clamped in a haemostat, divided and ligated. When the mesoappendix is broad the procedure must be repeated with a second, or rarely, a third haemostat. The appendix, now completely freed, is crushed near its junction with the caecum in a haemostat, which is removed and reapplied just distal to the crushed portion. An absorbable 2/0 ligature is tied around the crushed portion close to the caecum. The appendix is amputated between the haemostat and the ligature. An absorbable 2/0 or 3/0 purse-string or ‘Z’ suture may then be inserted into the caecum about 1 cm from the base. The stitch should pass through the muscle coat, picking up the taeniae coli. The stump of the appendix is invaginated while the purse-string or ‘Z’ suture is tied, thus burying the appendix stump. Many surgeons believe that invagination of the appendiceal stump is unnecessary.

Methods to be adopted in special circumstances

When the caecal wall is oedematous, the purse-string suture is in danger of cutting out. If the oedema is of limited extent this can be overcome by inserting the purse-string suture into more healthy caecal wall at a greater distance from the base of the appendix. Occasions may arise when, because of the extensive oedema of the caecal wall, it is better not to attempt invagination.
When the base of the appendix is inflamed, it should not be crushed but ligated close to the caecal wall just tightly enough to occlude the lumen, after which the appendix is amputated and the stump invaginated. Should the base of the appendix be gangrenous, neither crushing nor ligation must be attempted. Two stitches are placed through the caecal wall close to the base of the gangrenous appendix, which is amputated flush with the caecal wall, after which these stitches are tied. Further closure is effected by means of a second layer of interrupted seromuscular sutures.

Retrograde appendicectomy

When the appendix is retrocaecal and adherent, it is an advantage to divide the base between haemostats. The appendiceal vessels are then ligated, the stump is ligated and invaginated, and gentle traction on the caecum will enable the surgeon to deliver the body of the appendix which is then removed from base to tip. Occasionally, this manoeuvre requires division of the lateral peritoneal attachments of the caecum.

Drainage of the peritoneal cavity

This is usually unnecessary provided adequate peritoneal toilet has been done. If, however, there is considerable purulent fluid in the retrocaecal space or the pelvis, a soft silastic drain may be inserted through a separate stab incision. The wound should be closed using absorbable sutures to oppose muscles and aponeurosis. In the presence of soiling or if a gangrenous appendix has been delivered through the wound, it is often wise to leave open or to delay primary closure by inserting a gauze wick between interrupted skin sutures (Brady).

Laparoscopic appendicectomy

The most valuable aspect of laparoscopy in the management of suspected appendicitis is as a diagnostic tool, particularly in women of child-bearing age. In general, an open technique should be used to establish a pneumoperitoneum, and for insertion of the laparoscopic ports as it is safer than the closed techniques using a Verres needle. The placement of the operating port may vary according to operator preference and previous abdominal scars. The operator stands to the patient’s left and faces a video monitor placed at the patient’s right foot. A moderate Trendelenberg tilt of the operating table assists delivery of loops of small bowel from the pelvis. The appendix is found in the conventional manner
by identification of the caecal taeniae and is controlled using laparoscopic tissue-holding forceps. By elevating the appen­dix the mesoappendix is displayed. A dissecting forceps is used to create a window in the mesoappendix to allow the appendicular vessels to be coagulated or ligated using a clip applicator. The appendix, free of its mesentery, can be ligated at its base with an absorbable loop ligature, divided and removed through one of the operating ports. It is not usual to invert the stump of the appendix. A single absorbable suture is used to close the linea alba at the umbilicus and the small skin incisions may be closed with a subcuticular suture.
Patients who undergo laparoscopic appendicectomy are likely to be discharged from hospital and return to work slightly sooner than those who have undergone open appendicectomy, but it remains to be seen whether this justifies the slightly longer operating time and higher costs involved.

Problems encountered during appendicectomy

• A normal appendix is found — this demands careful exclusion of other possible diagnoses, particularly terminal ileitis, Meckel’s diverticulitis and tubal or ovarian causes in women. It is usual to remove the appendix to avoid future diagnostic difficulties, even though the appendix is macroscopically normal, particularly if a skin crease or grid-iron incision has been made. A case can be made for preserving the macroscopically normal appendix seen at diagnostic laparoscopy, although approximately a quarter of seemingly normal appendices show microscopic evidence of inflammation.
• The appendix cannot be found — the caecum should he mobilised and the taenia coli should be traced to their confluence on the caecum before the diagnosis of ‘absent appendix’ is made.
• An appendicular tumour is found — small tumours (under 2.0 cm in diameter) can he removed by appendicectomy; larger tumours should he treated by a right hemicolectomy.
• An appendix abscess is found and the appendix cannot he removed easily — this should be treated by local peritoneal toilet, drainage of any abscess and intravenous antibiotics. Very rarely a caecectomy or partial right hemicolectomy is required. (The first recorded operation for an appendix abscess was by Henry Hancock of Charing Cross Hospital, London, in 1848.)
Appendicitis complicating Crohn’s disease
Occasionally, a patient is operated on for acute appendicitis who is found to have concomitant Crohn’s disease of the ileo-caecal region. Providing the caecal wall is healthy at the base of the appendix, appendicectomy can he performed without increasing the risk of an enterocutaneous fistula. Rarely, the appendix is involved with the Crohn’s disease. In this situation a conservative approach may be warranted, and a trial of intravenous corticosteroids and systemic antibiotics used to resolve the acute inflammatory process.

Appendix abscess

Failure of resolution of an appendix mass or continued spiking pyrexia usually indicates that there is pus within the phlegmonous appendix mass. Ultrasound or abdominal CT scan may identify an area suitable for insertion of a percutaneous drain. Should this prove unsuccessful, laparotomy through a midline incision is indicated.

Pelvic abscess

Pelvic abscess formation is an occasional complication of appendicitis and can occur irrespective of the position of the appendix within the peritoneal cavity. The most common presentation is a spiking pyrexia several days following appendicitis; indeed the patient may have already been discharged from hospital. Pelvic pressure or discomfort associated with loose stool or tenesmus is common. Rectal examination reveals a buggy mass in the pelvis, anterior to the rectum, at the level of the peritoneal reflection. Pelvic ultrasound or CT scan will confirm. Treatment is transrectal drainage under general anaesthetic.

Management of an appendix mass

If an appendix mass is present and the condition of the patient is satisfactory, the standard treatment is the conservative Ochsner—Sherren regimen. This strategy is based on the premise that the inflammatory process is already localised and that inadvertent surgery is difficult and may be dangerous. It may be impossible to find the appendix and, occasionally, a faecal fistula may form. For these reasons it is wise to observe a nonoperative programme, but to be prepared to operate should clinical deterioration occur.
Careful record of the patient’s condition and the extent of the mass should be made, and the abdomen regularly re­examined. It is helpful to mark the limits of mass on the abdominal wall using a skin pencil. A nasogastric tube should be passed and intravenous fluid and antibiotic therapy instigated. Temperature and pulse rate should be recorded 4-hourly and a fluid balance record maintained. Clinical deterioration or evidence of peritonitis is indication for early laparotomy. Clinical improvement is usually evident within 24—48 hours at which time the nasogastric tube can be removed and oral fluids introduced. Failure of the mass to resolve should raise suspicion of a carcinoma or Crohn’s disease. Using this regime approximately 90 per cent of cases resolve without incident. It is advisable to remove the appendix usually after an interval of 6—8 weeks.

Postoperative complications

Postoperative complications following appendicectomy are relatively uncommon and reflect the degree of peritonitis that was present at the time of operation and intercurrent diseases that may predispose to complications.
Wound infection
This is the most common postoperative complication which occurs in 5—10 per cent of all cases. This usually presents with pain and erythema of the wound on the fourth or fifth postoperative day, often soon after hospital discharge.Treatment is by wound drainage and antibiotics when required. The organisms responsible are usually a mixture of Gram-negative bacilli and anaerobic bacteria, predominantlyBacteroides species and anaerobic streptococci.

Intra-abdominal abscess

Intra-abdominal abscess has become a relatively rare complication after appendicectomy with the use of perioperative antibiotics. Postoperative spiking fever, malaise and anorexia, developing 5—7 days after operation, suggest an intraperi­toneal collection. Interloop, paracolic, pelvic and subphrenic sites should be considered. Abdominal ultrasonography and CT scanning greatly facilitate diagnosis and allow percuta­neous drainage. Laparotomy should be considered in patients suspected to have intrabdominal sepsis in whom imaging fails to show a collection, particularly those with continuing ileus.

Ileus

A period of adynamic ileus is to be expected after appen­dicectomy, and may last for a number of days following removal of a gangrenous appendix. Ileus persisting for more than 4—5 days, particularly in the presence of a fever, is indicative of continuing intra-abdominal sepsis and should prompt further investigation (see above).

Respiratory

In the absence of concurrent pulmonary disease, respiratory complications are rare following appendicectomy. Adequate postoperative analgesia and physiotherapy, when appropriate, reduce the incidence.

Venous thrombosis and embolism

These are rare after appendicectomy except in the elderly and women taking the oral contraceptive pill. Appropriate prophylactic measures should be taken in such cases.
Portal pyaemia (Pylephlebitis)
Pylephlebitis is a rare but very serious complication of gangrenous appendicitis associated with high fever, rigors and jaundice. It is due to septicaemia in the portal venous system and may leads to the development of intrahepatic abscesses (often multiple). Treatment is with systemic antibiotics and percutaneous drainage of hepatic abscesses as appropriate.

Faecal fistula

Leakage from the appendicular stump rarely occurs, but may follow if the encircling stitch has been put in too deeply or if the caecal wall was involved by oedema or inflammation. Occasionally, a fistula may result following appendicectomy in Crohn’s disease.

Adhesive intestinal obstruction

Adhesive intestinal obstruction is the most common late complication of appendicectomy. At operation often a single band adhesion is responsible. Occasionally, chronic pain in the right iliac fossa is attributed to adhesion formation after appendicectomy. In such cases laparoscopy is of value in confirming the presence of adhesions and allowing division.

Right inguinal hernia

This is said to be more common following a grid-iron incision for appendicitis due to injury to the iliohypogastric nerve.

Recurrent acute appendicitis

Appendicitis is notoriously recurrent. It is not uncommon for patients to attribute such attacks to ‘biliousness’ or dyspepsia. The attacks vary in intensity, may occur every few months and the majority of cases ultimately culminate in severe acute appendicitis. If a careful history is taken from patients with acute appendicitis many remember having had milder but similar attacks of pain. The appendix in these cases shows fibrosis indicative of previous inflammation. Chronic appendicitis, per se, does not exist. Patients labelled thus are usually examples of the recurrent form of the disease.

Less common pathological conditions

Mucocele of the appendix

Mucocele of the appendix may occur when the proximal end of the lumen slowly becomes completely occluded, usually by a fibrous stricture, and the pent up secretion remains sterile. The appendix is greatly enlarged and sometimes it contains several millilitres of mucus.The symptoms produced are those of mild subacute appendicitis unless infection supervenes, when the mucocele is converted into an empyema.Rupture of a mucocele of the appendix is a cause of pseudomyxoma peritonei. Occasionally, the mucocele is caused by a mucus secreting adenocarcinoma, in which case a right hemicolectomy is the correct treatment.

Diverticulae of the appendix

Diverticulosis of the appendix is relatively rare and the diverticulae may be true congenital (all coats) or acquired (no muscularis layer). The condition may occur in conjunction with mucocele, in which case the intramural pressure rises sufficiently to cause herniation of the mucous membrane through the muscle coat at several points. More often, there is no demonstrable obstruction to the lumen. The patient usually gives a history of previous recurrent attacks of appendicitis. If encountered during the course of an operation for another condition, a diverticulae­bearing appendix should be removed because of a propensity to perforate if inflamed.

Intussusception of the appendix

This is rare and occurs mostly in childhood. It can he diagnosed only at operation. The symptoms usually are not acute. Untreated, the condition may pass on to an appendiculocolic intussusception. The appendix may slough, and this accounts for most of the very rare cases in which the appendix is absent. The treatment is appendicectomy.

Neoplasms of the appendix

Carcinoid tumour (syn. argentaffinoma)

Carcinoid tumours arise in argentaffin tissue (Kulschitzsky cells of the crypts of Lieberkuhn) and are most commonly found in the vermiform appendix. Carcinoid tumour is found once in every 300—400 appendices subjected to histological examination and is 10 times more common than any other neoplasm of the appendix. In many instances the appendix had been removed because of symptoms of subacute or recurrent appendicitis. The tumour can occur in any part of the appendix, but it frequently does so in the distal third. The neoplasm feels moderately hard, and on sectioning the appendix it can be seen as a yellow tumour between the intact mucosa and the peritoneum. Microscopically, the tumour cells are small, arranged in small nests within the muscle and have a characteristic pattern using immunohistochemical stain for Chromogranin B. Unlike carcinoid tumours arising in other parts of the intestinal tract, carcinoid tumour of the appendix rarely gives rise to metastases. Appendicectomy has been shown to be sufficient treatment, unless the caecal wall is involved, the tumour is 2 cm or more in size, or involved lymph nodes are found, otherwise right hemicolectomy is indicated.

Primary adenocarcinoma

Primary adenocarcinoma of the appendix is extremely rare. It is usually of the colonic type and should be treated by right hemicolectomy (as a second-stage procedure if the condition is not recognised at the first operation).

Corneal Ulcer

Corneal Ulcer

Synonyms and Related Keywords

Bacterial keratitis, Fungal keratitis, Acanthamoeba keratitis, Herpes simplex keratitis, corneal infection, open sore on the cornea, contact lenses, contact lens wearers, ulcerative keratitis




What is corneal ulcer ?

A corneal ulcer is an erosion or open sore in the outer layer of the cornea the clear structure overlying the iris (which is the colored part of your eye). It is common associated with infection by a bacterium, virus, fungus, or parasite.The corneal ulcer, or ulcerative keratitis, is an inflammatory or more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans particularly in the tropics and the agrarian societies. In developing countries, corneal ulcer is frequently the cause of great morbidity as well as economic loss to the person and family. Children afflicted by Vitamin A deficiency are at high risk for corneal ulcer and may become blind in both eyes, which may persist lifelong, causing tremendous & avoidable loss to the person and the society.



Corneal anatomy of the human

The cornea is a transparent structure that is part of the outer layer of the eye. It refracts light and protects the contents of the eye. The corneal thickness ranges from 450 to 610 micrometres and on an average 550 µm. thick in caucasian eyes. In Indian eyes, the average thickness is slightly less at 510 µm. The trigeminal nerve supplies the cornea via the long ciliary nerves. There are pain receptors in the outer layers and pressure receptors are deeper.
Transparency is achieved through a lack of blood vessels, pigmentation, and keratin, and through tight layered organization of the collagen fibers. The collagen fibers cross the full diameter of the cornea in a strictly parallel fashion and allow 99 percent of the light to pass through without scattering.
There are five layers in the human cornea, from outer to inner:
Epithelium
Bowman's layer
Stroma
Descemet's membrane
Endothelium
The outer layer is the epithelium, which is 25 to 40 µm micrometers and five to seven cell layers thick. The epithelium holds the tear film in place and also prevents water from invading the cornea and disrupting the collagen fibers. This prevents corneal edema, which gives it a cloudy appearance. It is also a barrier to infectious agents. The epithelium sticks to the basement membrane, which also separates the epithelium from the stroma. The corneal stroma comprises 90 percent of the thickness of the cornea. It contains the collagen fibers organized into lamellae. The lamellae are in sheets which separate easily. Posterior to the stroma is Descemet's membrane, which is a basement membrane for the corneal endothelium. The endothelium is a single cell layer that separates the cornea from the aqueous humor.

Most Commmon cause of corneal ulcers are caused by infections.

Corneal ulcers are most commonly caused by an infection with bacteria, viruses, fungi or amoebae. Other causes are abrasions (scratches) or foreign bodies, inadequate eyelid closure, severely dry eyes, severe allergic eye disease, and various inflammatory disorders.
Contact lens wear, especially soft contact lenses worn overnight, may cause a corneal ulcer. Herpes simplex keratitis is a serious viral infection. It may cause repeated attacks that are triggered by stress, exposure to sunlight, or any condition that impairs the immune system. Bacterial infections cause corneal ulcers and are common in people who wear contact lenses. Fungal keratitis can occur after a corneal injury involving plant material, or in immunosuppressed people. Acanthamoeba keratitis occurs in contact lens users, especially those who attempt to make their own homemade cleaning solutions.Fungal infections can cause corneal ulcers and may develop with improper care of contact lenses or the overuse of eyedrops that contain steroids.
Viral infections are also possible causes of corneal ulcers. Such viruses include the herpes simplex virus (the virus that causes cold sores) or the varicella virus (the virus that causes chickenpox and shingles).
Tiny tears to the corneal surface may become infected and lead to corneal ulcers. These tears can come from direct trauma by scratches or metallic or glass particles striking the cornea. Such injuries damage the corneal surface and make it easier for bacteria to invade and cause a corneal ulcer.
Disorders that cause dry eyes can leave your eye without the germ-fighting protection of tears and cause ulcers.
Disorders that affect the eyelid and prevent your eye from closing completely, such as Bell's palsy, can dry your cornea and make it more vulnerable to ulcers.
Any condition which causes loss of sensation of the corneal surface may increase the risk of corneal ulceration.
Chemical burns or other caustic (damaging) solution splashes can injure the cornea and lead to corneal ulceration.
People who wear contact lenses are at an increased risk of corneal ulcers. The risk of corneal ulcerations increases tenfold when using extended-wear soft contact lenses. Extended-wear contact lenses refer to those contact lenses that are worn for several days without removing them at night. Contact lenses may damage your cornea in many ways:
Scratches on the edge of your contact lens can scrape the cornea's surface and make it more vulnerable to bacterial infections.
Similarly, tiny particles of dirt trapped underneath the contact lens can scratch the cornea.
Bacteria may be on the improperly cleaned lens and get trapped on the undersurface of the lens. If your lenses are left in your eyes for long periods of time, these bacteria can multiply and cause damage to the cornea.
Wearing lenses for extended periods of time can also block oxygen to the cornea, making it more susceptible to infections.
Risk factors are dry eyes, severe allergies, history of inflammatory disorders, contact lens wear, immunosuppression, trauma, and generalized infection.

Corneal Ulcer Symptoms

Eye pain
Impaired vision, Blurry vision
Eye redness( red eye)
White patch on the cornea
Sensitivity to light (photophobia)
Watery eyes, Tearing
Eye burning, itching and discharge
Feeling that something is in your eye
Pus or thick discharge draining from your eye
Pain when looking at bright lights
Swollen eyelids
A white or gray round spot on the cornea that is visible with the naked eye if the ulcer is large

Diagnosis of Corneal ulcer

Because corneal ulcers are a serious problem, you should see your ophthalmologist (a medical doctor who specializes in eye care and surgery).
Your ophthalmologist will be able to detect if you have an ulcer by using a special eye microscope, known as a slit lamp. To make the ulcer easier to see, he or she will put a drop containing the dye fluorescein into your eye.
If your ophthalmologist thinks that an infection is responsible for the ulcer, he or she may then get samples of the ulcer to send to the laboratory for identification.
Visual acuity
Tear test
Slit-lamp examination
Pupillary reflex response
Keratometry (measurement of the cornea)
Scraping the ulcer for analysis or culture
Fluorescein stain of the cornea
Blood tests to check for inflammatory disorders may also be needed.
Diagnosis is done by direct observation under magnified view of slit lamp revealing the ulcer on the cornea. The use of fluorescein stain, which is taken up by exposed corneal stroma and appears green, helps in defining the margins of the corneal ulcer, and can reveal additional details of the surrounding epithelium. Herpes simplex ulcers show a typical dendritic pattern of staining. Rose-Bengal dye is also used for supra-vital staining purposes, but it may be very irritating to the eyes. In descemetoceles, the Descemet's membrane will bulge forward and after staining will appear as a dark circle with a green boundary, because it does not absorb the stain. Doing a corneal scraping and examining under the microscope with stains like Gram's and KOH preparation may reveal the bacteria and fungi respectively. Microbiological culture tests may be necessary to isolate the causative organisms for some cases. Other tests that may be necessary include a Schirmer's test for keratoconjunctivitis sicca and an analysis of facial nerve function for facial nerve paralysis.

Treatment

Proper diagnosis is essential for optimal treatment. Bacterial corneal ulcer require intensive fortified antibiotic therapy to treat the infection. Fungal corneal ulcers require intensive application of topical anti-fungal agents. Viral corneal ulceration caused by herpes virus may antivirals like topical acyclovir oint instilled at least five times a day. Alongside, supportive therapy like pain medications are given, including topical cycloplegics like atropine or homatropine to dilate the pupil and thereby stop spasms of the ciliary muscle. Superficial ulcers may heal in less than a week. Deep ulcers and descemetoceles may require conjunctival grafts or conjunctival flaps, soft contact lenses, or corneal transplant. Proper nutrition, including protein intake and Vitamin C are usually advised. In cases of Keratomalacia, where the corneal ulceration is due to a deficiency of Vitamin A, supplementation of the Vitamin A by oral or intramuscular route is given. Drugs that are usually contraindicated in corneal ulcer are topical corticosteroids and anesthetics - these should not be used on any type of corneal ulcer because they prevent healing, may lead to superinfection with fungi and other bacteria and will often make the condition much worse.
So can conclude that how to treatment corneal ulcer
Self-Care at Home

If you wear contact lenses, remove them immediately.
Apply cool compresses to the affected eye.
Do not touch or rub your eye with your fingers.
Limit spread of infection by washing your hands often and drying them with a clean towel.
Take over-the-counter pain medications, such as acetaminophen or ibuprofen.

Medical Treatment
Your ophthalmologist will remove your contact lenses if you are wearing them.
Your ophthalmologist will generally not place a patch over your eye if he or she suspects that you have a bacterial infection. Patching creates a warm dark environment that allows bacterial growth.
Hospitalization may be required if the ulcer is severe

Prognosis of corneal ulcer

Untreated, a corneal ulcer or infection can permanently damage the cornea. Untreated corneal ulcers may also perforate the eye (cause holes), resulting in spread of the infection inside, increasing the risk of permanent visual problems.

Possible Complications of corneal ulcer

Corneal scarring
Severe vision loss
Loss of the eye

Prevention of corneal ulcer

Prompt, early attention by an ophthalmologist for an eye infection may prevent the condition from worsening to the point of ulceration. Wash hands and pay rigorous attention to cleanliness while handling contact lenses, and avoid wearing contact lenses overnight.

Hormones

Hypothalamic and Hypophyseal Hormones

The endocrine system is controlled by the brain. Nerve cells of the hypothalamus
synthesize and release messenger substances that regulate adenohypophyseal
(AH) hormone release or are themselves secreted into the body as
hormones. The latter comprise the socalled neurohypophyseal (NH) hormones.
The axonal processes of hypothalamic neurons project to the neurohypophysis,
where they store the nonapeptides vasopressin (= antidiuretic hormone,
ADH) and oxytocin and release them on demand into the blood. Therapeutically
(ADH, oxytocin), these peptide hormones are given parenterally
or via the nasal mucosa. The hypothalamic releasing hormones
are peptides. They reach their target cells in the AH lobe by way of a
portal vascular route consisting of two serially connected capillary beds. The
first of these lies in the hypophyseal stalk, the second corresponds to the
capillary bed of the AH lobe. Here, the hypothalamic hormones diffuse from
the blood to their target cells, whose activity they control. Hormones released
from the AH cells enter the blood, in which they are distributed to peripheral
organs.
Nomenclature of releasing hormones:
RH–releasing hormone; RIH—release inhibiting hormone.
GnRH: gonadotropin-RH = gonadorelin stimulates the release of FSH
(follicle-stimulating hormone) and LH (luteinizing hormone).
TRH: thyrotropin-RH (protirelin) stimulates the release of TSH (thyroid
stimulating hormone = thyrotropin). CRH: corticotropin-RH stimulates
the release of ACTH (adrenocorticotropic hormone = corticotropin).
GRH: growth hormone-RH (somatocrinin) stimulates the release of GH
(growth hormone = STH, somatotropic hormone). GRIH somatostatin inhibits
release of STH (and also other peptide hormones including insulin, glucagon,
and gastrin). PRH: prolactin-RH remains to be
characterized or established. Both TRH and vasoactive intestinal peptide (VIP)
are implicated. PRIH inhibits the release of prolactin
and could be identical with dopamine. Hypothalamic releasing hormones
are mostly administered (parenterally) for diagnostic reasons to test AH function.
Therapeutic control of AH cells. GnRH is used in hypothalamic infertility
in women to stimulate FSH and LH secretion and to induce ovulation. For this
purpose, it is necessary to mimic the physiologic intermittent “pulsatile” release
(approx. every 90 min) by means of a programmed infusion pump.
Gonadorelin superagonists are GnRH analogues that bind with very
high avidity to GnRH receptors of AH cells. As a result of the nonphysiologic
uninterrupted receptor stimulation, initial augmentation of FSH and LH output
is followed by a prolonged decrease. Buserelin, leuprorelin, goserelin, and triptorelin
are used in patients with prostatic carcinoma to reduce production of
testosterone, which promotes tumor growth. Testosterone levels fall as much
as after extirpation of the testes. The dopamine D2 agonists bromocriptine
and cabergoline inhibit prolactin-releasing AH cells (indications:
suppression of lactation, prolactin-producing tumors). Excessive,
but not normal, growth hormone release can also be inhibited (indication:
acromegaly).
Octreotide is a somatostatin analogue; it is used in the treatment of
somatostatin-secreting pituitary tumors.

Thyroid Hormone Therapy
Thyroid hormones accelerate metabolism.Their release is regulated by
the hypophyseal glycoprotein TSH,whose release, in turn, is controlled by
the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of
thyroid hormones rises; by means of this negative feedback mechanism, hormone
production is “automatically” adjusted to demand.
The thyroid releases predominantly thyroxine (T4). However, the active form
appears to be triiodothyronine (T3); T4 is converted in part to T3, receptor affinity
in target organs being 10-fold higher for T3. The effect of T3 develops more rapidly
and has a shorter duration than does that of T4. Plasma elimination t1/2 for T4
is about 7 d; that for T3, however, is only 1.5 d. Conversion of T4 to T3 releases iodide;
150 μg T4 contains 100 μg of iodine. For therapeutic purposes, T4 is chosen,
although T3 is the active form and better absorbed from the gut. However,
with T4 administration, more constant blood levels can be achieved because
degradation of T4 is so slow. Since absorption of T4 is maximal from an empty
stomach, T4 is taken about 1/2 h before breakfast.
Replacement therapy of hypothyroidism. Whether primary, i.e., caused
by thyroid disease, or secondary, i.e., resulting from TSH deficiency, hypothyroidism
is treated by oral administration of T4. Since too rapid activation of
metabolism entails the hazard of cardiac overload (angina pectoris, myocardial
infarction), therapy is usually started with low doses and gradually increased.
The final maintenance dose required to restore a euthyroid state depends
on individual needs (approx.150 μg/d).

Thyroid suppression therapy of euthyroid goiter. The cause of goiter
(struma) is usually a dietary deficiencyof iodine. Due to an increased
TSH action, the thyroid is activated to raise utilization of the little iodine available
to a level at which hypothyroidism is averted. Therefore, the thyroid increases
in size. In addition, intrathyroid depletion of iodine stimulates growth.
Because of the negative feedback regulation of thyroid function, thyroid
activation can be inhibited by administration of T4 doses equivalent to the endogenous
daily output (approx. 150 μg/d). Deprived of stimulation, the
inactive thyroid regresses in size.If a euthyroid goiter has not persisted
for too long, increasing iodine supply (potassium iodide tablets) can also be
effective in reversing overgrowth of the gland.
In older patients with goiter due to iodine deficiency there is a risk of provoking
hyperthyroidism by increasing iodine intake : During chronic
maximal stimulation, thyroid follicles can become independent of TSH stimulation
(“autonomic tissue”). If the iodine supply is increased, thyroid hormone
production increases while TSH secretion decreases due to feedback inhibition.
The activity of autonomic tissue, however, persists at a high level; thyroxine
is released in excess, resulting in iodine-induced hyperthyroidism.
Iodized salt prophylaxis. Goiter is endemic in regions where soils are deficient
in iodine. Use of iodized table salt allows iodine requirements (150–
300 μg/d) to be met and effectively prevents goiter.
is treated by oral administration of T4. Since too rapid activation of
metabolism entails the hazard of cardiac overload (angina pectoris, myocardial
infarction), therapy is usually started with low doses and gradually increased.
The final maintenance dose required to restore a euthyroid state depends
on individual needs (approx. 150 μg/d).

Hyperthyroidism and Antithyroid Drugs
Thyroid overactivity in Graves’ disease results from formation of IgG antibodies
that bind to and activate TSH receptors. Consequently, there is overproduction
of hormone with cessation of TSH secretion. Graves’ disease can abate
spontaneously after 1–2 y. Therefore,initial therapy consists of reversible
suppression of thyroid activity by means of antithyroid drugs. In other
forms of hyperthyroidism, such as hormone-producing (morphologically benign)
thyroid adenoma, the preferred therapeutic method is removal of tissue,
either by surgery or administration of 131iodine in sufficient dosage. Radioiodine
is taken up into thyroid cells and destroys tissue within a sphere of a few
millimeters by emitting !-(electron) particles during its radioactive decay.
Concerning iodine-induced hyperthyroidism. Antithyroid drugs inhibit thyroid
function. Release of thyroid hormone is preceded by a chain of events. A
membrane transporter actively accumulates iodide in thyroid cells; this is
followed by oxidation to iodine, iodination of tyrosine residues in thyroglobulin,
conjugation of two diiodotyrosine groups, and formation of T4 and T3
moieties. These reactions are catalyzed by thyroid peroxidase, which is localized
in the apical border of the follicular cell membrane. T4-containing thyroglobulin
is stored inside the thyroid follicles in the form of thyrocolloid. Upon
endocytotic uptake, colloid undergoes lysosomal enzymatic hydrolysis, enabling
thyroid hormone to be released as required. A “thyrostatic” effect can result
from inhibition of synthesis or release. When synthesis is arrested, the
antithyroid effect develops after a delay, as stored colloid continues to be utilized.
Antithyroid drugs for long-term therapy. Thiourea derivatives
(thioureylenes, thioamides) inhibit peroxidase and, hence, hormone synthesis.
In order to restore a euthyroid state, two therapeutic principles can be
applied in Graves’ disease: a) monotherapy with a thioamide with gradual dose
reduction as the disease abates) administration of high doses of a thioamide
with concurrent administration of thyroxine to offset diminished hormone
synthesis. Adverse effects of thioamides are rare; however, the possibility
of agranulocytosis has to be kept in mind.
Perchlorate, given orally as the sodium salt, inhibits the iodide pump. Adverse
reactions include aplastic anemia. Compared with thioamides, its therapeutic
importance is low but it is used as an adjunct in scintigraphic imaging of
bone by means of technetate when accumulation in the thyroid gland has
to be blocked.

Short-term thyroid suppression.
Iodine in high dosage (>6000 μg/d) exerts a transient “thyrostatic” effect in
hyperthyroid, but usually not in euthyroid, individuals. Since release is also
blocked, the effect develops more rapidly than does that of thioamides.
Clinical applications include: preoperative suppression of thyroid secretion
according to Plummer with Lugol’s solution (5% iodine + 10% potassium iodide,
50–100 mg iodine/d for a maximum of 10 d). In thyrotoxic crisis, Lugol’s solution
is given together with thioamides and !-blockers. Adverse effects: allergies;
contraindications: iodine-induced thyrotoxicosis.
Lithium ions inhibit thyroxine release. Lithium salts can be used instead
of iodine for rapid thyroid suppression in iodine-induced thyrotoxicosis. Regarding
administration of lithium in manic-depressive illness.

Glucocorticoid Therapy
I. Replacement therapy. The adrenal cortex (AC) produces the glucocorticoid
cortisol (hydrocortisone) and the mineralocorticoid aldosterone. Both steroid
hormones are vitally important in adaptation responses to stress situations,
such as disease, trauma, or surgery. Cortisol secretion is stimulated by hypophyseal
ACTH, aldosterone secretion by angiotensin II in particular. In
AC failure (primary AC insuffiency: Addison’s disease), both cortisol and aldosterone
must be replaced; when ACTH production is deficient (secondary AC insufficiency),
cortisol alone needs to be replaced. Cortisol is effective when given
orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In stress situations, the dose is raised by
5- to 10-fold. Aldosterone is poorly effective via the oral route; instead,
the mineralocorticoid fludrocortisone (0.1 mg/d) is given.
II. Pharmacodynamic therapy
with glucocorticoids . In unphysiologically high concentrations, cortisol or
other glucocorticoids suppress all phases(exudation, proliferation, scar formation)
of the inflammatory reaction, i.e.,the organism’s defensive measures
against foreign or noxious matter. This effect is mediated by multiple components,
all of which involve alterations in gene transcription. Glucocorticoids
inhibit the expression of genes encoding for proinflammatory proteins
(phospholipase-A2, cyclooxygenase 2,IL-2-receptor). The expression of these
genes is stimulated by the transcription factor NF!B. Binding to the glucocorticoid
receptor complex prevents translocation af NF!B to the nucleus. Conversely,
glucocorticoids augment the expression of some anti-inflammatory proteins,
e.g., lipocortin, which in turn inhibits phospholipase A2. Consequently,
release of arachidonic acid is diminished, as is the formation of inflammatory
mediators of the prostaglandin and leukotriene series . At very high
dosage, nongenomic effects may also contribute.
Desired effects. As anti-allergics, immunosuppressants, or anti-inflammatory
drugs, glucocorticoids display excellent efficacy against “undesired” inflammatory
reactions. Unwanted effects. With short-term
use, glucocorticoids are practically free of adverse effects, even at the highest
dosage. Long-term use is likely to cause changes mimicking the signs of
Cushing’s syndrome (endogenous overproduction of cortisol). Sequelae of
the anti-inflammatory action: lowered resistance to infection, delayed wound
healing, impaired healing of peptic ulcers. Sequelae of exaggerated glucocorticoid
action: a) increased gluconeogenesis and release of glucose; insulin-dependent
conversion of glucose to triglycerides(adiposity mainly noticeable in
the face, neck, and trunk); “steroid-diabetes” if insulin release is insufficient;
b) increased protein catabolism with atrophy of skeletal musculature (thin
extremities), osteoporosis, growth retardation in infants, skin atrophy. Sequelae
of the intrinsically weak, but now manifest, mineralocorticoid action
of cortisol: salt and fluid retention, hypertension, edema; KCl loss with danger
of hypokalemia. Measures for Attenuating or Preventing
Drug-Induced Cushing’s Syndrome a) Use of cortisol derivatives with less
(e.g., prednisolone) or negligible mineralocorticoid activity (e.g., triamcinolone,
dexamethasone). Glucocorticoid activity of these congeners is more pronounced.
Glucorticoid, anti-inflammatory and feedback inhibitory actions
on the hypophysis are correlated. An exclusively anti-inflammatory congener
does not exist. The “glucocorticoid” related Cushingoid symptoms
cannot be avoided. The table lists relative activity (potency) with reference to
cortisol, whose mineralo- and glucocorticoid activities are assigned a value of
1.0. All listed glucocorticoids are effective orally.

b) Local application. Typical adverse effects, however, also occur locally, e.g.,
skin atrophy or mucosal colonization with candidal fungi. To minimize
systemic absorption after inhalation, derivatives should be used that have a
high rate of presystemic elimination, such as beclomethasone dipropionate,
flunisolide, budesonide, or fluticasone propionate .
b) Lowest dosage possible. For longterm medication, a just sufficient dose
should be given. However, in attempting to lower the dose to the minimal effective
level, it is necessary to take into account that administration of exogenous
glucocorticoids will suppress production of endogenous cortisol due to
activation of an inhibitory feedback mechanism. In this manner, a very low
dose could be “buffered,” so that unphysiologically high glucocorticoid activity
and the anti-inflammatory effect are both prevented.
Effect of glucocorticoid administration on adrenocortical cortisol production
(A). Release of cortisol depends on stimulation by hypophyseal ACTH,
which in turn is controlled by hypothalamic corticotropin-releasing hormone
(CRH). In both the hypophysis and hypothalamus there are cortisol receptors
through which cortisol can exert a feedback inhibition of ACTH or CRH release.
By means of these cortisol “sensors,” the regulatory centers can monitor whether
the actual blood level of the hormone corresponds to the “set-point.” If the
blood level exceeds the set-point, ACTH output is decreased and, thus, also the
cortisol production. In this way cortisol level is maintained within the required
range. The regulatory centers respond to synthetic glucocorticoids as they do
to cortisol. Administration of exogenous cortisol or any other glucocorticoid reduces
the amount of endogenous cortisol needed to maintain homeostasis. Release
of CRH and ACTH declines ("inhibition of higher centers by exogenous
glucocorticoid”) and, thus, cortisol secretion (“adrenocortical suppression”).
After weeks of exposure to unphysiologically high glucocorticoid doses, the
cortisol-producing portions of the adrenal cortex shrink (“adrenocortical
atrophy”). Aldosterone-synthesizing capacity, however, remains unaffected.
When glucocorticoid medication is suddenly withheld, the atrophic cortex is
unable to produce sufficient cortisol and a potentially life-threatening cortisol
deficiency may develop. Therefore, glucocorticoid therapy should always be
tapered off by gradual reduction of the dosage.
Regimens for prevention of adrenocortical atrophy. Cortisol secretion
is high in the early morning and low in the late evening (circadian
rhythm). This fact implies that the regulatory centers continue to release CRH
or ACTH in the face of high morning blood levels of cortisol; accordingly,
sensitivity to feedback inhibition must be low in the morning, whereas the opposite
holds true in the late evening. a) Circadian administration: The
daily dose of glucocorticoid is given in the morning. Endogenous cortisol production
will have already begun, the regulatory centers being relatively insensitive
to inhibition. In the early morning hours of the next day, CRF/-
ACTH release and adrenocortical stimulation will resume.

b) Alternate-day therapy: Twice the daily dose is given on alternate mornings.
On the “off” day, endogenous cortisol production is allowed to occur.
The disadvantage of either regimen is a recrudescence of disease symptoms
during the glucocorticoid-free interval.

Androgens, Anabolic Steroids, Antiandrogens

Androgens are masculinizing substances. The endogenous male gonadal hormone
is the steroid testosterone from the interstitial Leydig cells of the testis.
Testosterone secretion is stimulated by hypophyseal luteinizing hormone (LH),
whose release is controlled by hypothalamic GnRH (gonadorelin). Release
of both hormones is subject to feedback inhibition by circulating testosterone.
Reduction of testosterone to dihydrotestosterone occurs in most target
organs; the latter possesses higher affinity for androgen receptors. Rapid
intrahepatic degradation (plasma t1/2 ~ 15 min) yields androsterone among
other metabolites (17-ketosteroids) that are eliminated as conjugates in the
urine. Because of rapid hepatic metabolism, testosterone is unsuitable for oral
use. Although it is well absorbed, it undergoes virtually complete presystemic
elimination. Testosterone (T.) derivatives for
clinical use. T. esters for i.m. depot injection are T. propionate and T. heptanoate
(or enanthate). These are given in oily solution by deep intramuscular injection.
Upon diffusion of the ester from the depot, esterases quickly split off the
acyl residue, to yield free T. With increasing lipophilicity, esters will tend to
remain in the depot, and the duration of action therefore lengthens. A T. ester for
oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this
ester is absorbed into the lymph, enabling it to bypass the liver and enter, via
the thoracic duct, the general circulation. 17-a Methyltestosterone is effective
by the oral route due to its increased metabolic stability, but because of the
hepatotoxicity of C17-alkylated androgens (cholestasis, tumors) its use should
be avoided. Orally active mesterolone is 1!-methyl-dihydrotestosterone. Transdermal
delivery systems for T. are also available.
Indications. For hormone replacement in deficiency of endogenous T.
production and palliative treatment of breast cancer, T. esters for depot injection
are optimally suited. Secondary sex characteristics and libido are maintained;
however, fertility is not promoted. On the contrary, spermatogenesis
may be suppressed because of feedback inhibition of hypothalamohypophyseal
gonadotropin secretion. Stimulation of spermatogenesis
in gonadotropin (FSH, LH) deficiency can be achieved by injection of HMG
and HCG. HMG or human menopausal gonadotropin is obtained from the urine
of postmenopausal women and is rich in FSH activity. HCG, human chorionic
gonadotropin, from the urine of pregnant women, acts like LH.
Anabolics are testosterone derivatives (e.g., clostebol, metenolone, nandrolone,
stanozolol) that are used in debilitated patients, and misused by athletes,
because of their protein anabolic effect. They act via stimulation of androgen
receptors and, thus, also display androgenic actions (e.g., virilization in females,
suppression of spermatogenesis). The antiandrogen cyproterone
acts as a competitive antagonist of T. In addition, it has progestin activity
whereby it inhibits gonadotropin secretion. Indications: in men, inhibition
of sex drive in hypersexuality; prostatic cancer. In women: treatment
of virilization, with potential utilization of the gestagenic contraceptive effect.
Flutamide, an androgen receptor antagonist possessing a different chemical
structure, lacks progestin activity. Finasteride inhibits 5!-reductase,
the enzyme converting T. into dihydrotestosterone (DHT). Thus, the androgenic
stimulus is reduced in those tissues in which DHT is the active species (e.g.,
prostate). T.-dependent tissues or functions are not or hardly affected (e.g.,
skeletal muscle, negative feedback inhibition of gonadotropin secretion, and libido).
Finasteride can be used in benign prostate hyperplasia to shrink the gland
and, possibly, to improve micturition.

Follicular Growth and Ovulation, Estrogen and Progestin Production

Follicular maturation and ovulation, as well as the associated production of female
gonadal hormones, are controlled by the hypophyseal gonadotropins FSH
(follicle-stimulating hormone) and LH (luteinizing hormone). In the first half of
the menstrual cycle, FSH promotes growth and maturation of ovarian follicles
that respond with accelerating synthesis of estradiol. Estradiol stimulates
endometrial growth and increases the permeability of cervical mucus for
sperm cells. When the estradiol blood level approaches a predetermined setpoint,
FSH release is inhibited due to feedback action on the anterior hypophysis.
Since follicle growth and estrogen production are correlated, hypophysis
and hypothalamus can “monitor” the follicular phase of the ovarian cycle
through their estrogen receptors. Within hours after ovulation, the tertiary follicle
develops into the corpus luteum, which then also releases progesterone
in response to LH. The former initiates the secretory phase of the endometrial
cycle and lowers the permeability of cervical mucus. Nonruptured follicles
continue to release estradiol under the influence of FSH. After 2 wk, production
of progesterone and estradiol subsides, causing the secretory endometrial layer
to be shed (menstruation).The natural hormones are unsuitable
for oral application because they are subject to presystemic hepatic elimination.
Estradiol is converted via estrone to estriol; by conjugation, all three
can be rendered water soluble and amenable to renal excretion. The major
metabolite of progesterone is pregnandiol, which is also conjugated and eliminated
renally. Estrogen preparations. Depot preparations for i.m. injection are oily
solutions of esters of estradiol (3- or 17- OH group). The hydrophobicity of the
acyl moiety determines the rate of absorption, hence the duration of effect.
Released ester is hydrolyzed to yield free estradiol.
Orally used preparations. Ethinylestradiol (EE) is more stable metabolically,
passes largely unchanged through the liver after oral intake and mimics estradiol
at estrogen receptors. Mestranol itself is inactive; however, cleavage of
the C-3 methoxy group again yields EE. In oral contraceptives, one of the two
agents forms the estrogen component. (Sulfate-)conjugated estrogens
can be extracted from equine urine and are used for the prevention of postmenopausal
osteoporosis and in the therapy of climacteric complaints. Because
of their high polarity (sulfate, glucuronide), they would hardly appear
suitable for this route of administration. For transdermal delivery, an adhesive
patch is available that releases estradiol transcutaneously into the body.
Progestin preparations. Depot formulations for i.m. injection are 17-
!-hydroxyprogesterone caproate and medroxyprogesterone acetate. Preparations
for oral use are derivatives of 17!- ethinyltestosterone = ethisterone (e.g.,
norethisterone, dimethisterone, lynestrenol,desogestrel, gestoden), or of
17!-hydroxyprogesterone acetate (e.g.,chlormadinone acetate or cyproterone
acetate). These agents are mainly used as the progestin component in oral contraceptives.
Indications for estrogens and progestins include: hormonal contraception
, hormone replacement, as in postmenopausal women for prophylaxis
of osteoporosis; bleeding anomalies, menstrual complaints. Concerning
adverse effects, see p.

Estrogens with partial agonist activity (raloxifene, tamoxifene) are being
investigated as agents used to replace estrogen in postmenopausal osteoporosis
treatment, to lower plasma lipids, and as estrogen antagonists in
the prevention of breast cancer. Raloxifen—in contrast to tamoxifen—is an antagonist
at uterine estrogen receptors.

Oral Contraceptives

Inhibitors of ovulation. Negative feedback control of gonadotropin release
can be utilized to inhibit the ovarian cycle. Administration of exogenous estrogens
(ethinylestradiol or mestranol) during the first half of the cycle permits
FSH production to be suppressed (as it is by administration of progestins
alone). Due to the reduced FSH stimulation of tertiary follicles, maturation of
follicles and, hence, ovulation are prevented. In effect, the regulatory brain
centers are deceived, as it were, by the elevated estrogen blood level, which
signals normal follicular growth and a decreased requirement for FSH stimulation.
If estrogens alone are given during the first half of the cycle, endometrial
and cervical responses, as well as other functional changes, would occur in the
normal fashion. By adding a progestin during the second half of the cycle,
the secretory phase of the endometrium and associated effects can be elicited.
Discontinuance of hormone administration would be followed by
menstruation. The physiological time course of estrogen-
progesterone release is simulated in the so-called biphasic (sequential)
preparations. In monophasic preparations, estrogen and progestin
are taken concurrently. Early administration of progestin reinforces the inhibition
of CNS regulatory mechanisms, prevents both normal endometrial
growth and conditions for ovum implantation, and decreases penetrability
of cervical mucus for sperm cells. The two latter effects also act to prevent
conception. According to the staging of progestin administration, one distinguishes
(A): one-, two-, and three-stage preparations. In all cases, “withdrawalbleeding”
occurs when hormone intake is discontinued (if necessary, by substituting
dummy tablets). Unwanted effects: An increased incidence
of thrombosis and embolism is attributed to the estrogen component in
particular. Hypertension, fluid retention, cholestasis, benign liver tumors,
nausea, chest pain, etc. may occur. Apparently there is no increased overall
risk of malignant tumors. Minipill. Continuous low-dose administration
of progestin alone can prevent conception. Ovulations are not
suppressed regularly; the effect is then due to progestin-induced alterations in
cervical and endometrial function. Because of the need for constant intake at
the same time of day, a lower success rate, and relatively frequent bleeding
anomalies, these preparations are now rarely employed.
“Morning-after” pill. This refers to administration of a high dose of estrogen
and progestin, preferably within 12 to 24 h, but no later than 72 h after coitus.
Menstrual bleeding ensues, which prevents implantation of the fertilized
ovum (normally on the 7th day after fertilization). Similarly, implantation
can be inhibited by mifepristone, which is an antagonist at both progesterone
and glucocorticoid receptors and which also offers a noninvasive means of inducing
therapeutic abortion in early pregnancy.
Stimulation of ovulation. Gonadotropin secretion can be increased by
pulsatile delivery of GnRH. The estrogen antagonists clomiphene and cyclofenil
block receptors mediating feedback inhibition of central neuroendocrine
circuits and thereby disinhibit gonadotropin release. Gonadotropins
can be given in the form of HMG and HCG .

Insulin Therapy

Insulin is synthesized in the B- (or !-) cells of the pancreatic islets of Langerhans.
It is a protein (MW 5800) consisting of two peptide chains linked by two
disulfide bridges; the A chain has 21 and the B chain 30 amino acids. Insulin is the
“blood-sugar lowering” hormone. Upon ingestion of dietary carbohydrates, it is
released into the blood and acts to prevent a significant rise in blood glucose
concentration by promoting uptake of glucose in specific organs, viz., the
heart, adipose tissue, and skeletal muscle, or its conversion to glycogen in the
liver. It also increases lipogenesis and protein synthesis, while inhibiting lipolysis
and release of free fatty acids. Insulin is used in the replacement
therapy of diabetes mellitus to supplement a deficient secretion of endogenous
hormone.
Sources of therapeutic insulin preparations (A). Insulin can be obtained
from pancreatic tissue of slaughtered animals. Porcine insulin differs
from human insulin merely by one B chain amino acid, bovine insulin by two
amino acids in the A chain and one in the B chain. With these slight differences,
animal and human hormone display similar biological activity. Compared
with human hormone, porcine insulin is barely antigenic and bovine insulin has
a little higher antigenicity. Human insulin is produced by two methods: biosynthetically,
by substituting threonine for the C-terminal alanine in the B chain of
porcine insulin; or by gene technology involving insertion of the appropriate
human DNA into E. coli bacteria. Types of preparations . As a
peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal
proteases) and thus needs to be given parenterally. Usually, insulin
preparations are injected subcutaneously. The duration of action depends
on the rate of absorption from the injection site.
Short-acting insulin is dispensed as a clear neutral solution known as
regular insulin. In emergencies, such as hyperglycemic coma, it can be given
intravenously (mostly by infusion because i.v. injections have too brief an action;
plasma t1/2 ~ 9 min). With the usual subcutaneous application, the effect
is evident within 15 to 20 min, reaches a peak after approx. 3 h, and lasts for approx.
6 h. Lispro insulin has a faster onset and slightly shorter duration of action.
Insulin suspensions. When the hormone is injected as a suspension of
insulin-containing particles, its dissolution and release in subcutaneous tissue
are retarded (rapid, intermediate, and slow insulins). Suitable particles can be
obtained by precipitation of apolar, poorly water-soluble complexes consisting
of anionic insulin and cationic partners, e.g., the polycationic protein
protamine or the compound aminoquinuride (Surfen). In the presence of zinc
and acetate ions, insulin crystallizes; crystal size determines the rate of dissolution.
Intermediate insulin preparations (NPH or isophane, lente or zinc insulin)
act for 18 to 26 h, slow preparations (protamine zinc insulin, ultralente
or extended zinc insulin) for up to 36 h. Combination preparations contain
insulin mixtures in solution and in suspension (e.g., ultralente); the plasma
concentration-time curve represents the sum of the two components.
Unwanted effects. Hypoglycemia results from absolute or relative overdosage
. Allergic reactions are rare—locally: redness at injection site,
atrophy of adipose tissue (lipodystrophy); systemically: urticaria, skin rash,
anaphylaxis. Insulin resistance can result from binding to inactivating antibodies.
A possible local lipohypertrophy can be avoided by alternating injection
sites.

Treatment of Insulin-Dependent Diabetes Mellitus

“Juvenile onset” (type I) diabetes mellitus is caused by the destruction of insulin-
producing B cells in the pancreas, necessitating replacement of insulin
(daily dose approx. 40 U, equivalent to approx. 1.6 mg).
Therapeutic objectives are: (1) prevention of life-threatening hyperglycemic
(diabetic) coma; (2) prevention of diabetic sequelae (angiopathy with
blindness, myocardial infarction, renal failure), with precise “titration” of the
patient being essential to avoid even short-term spells of pathological hyperglycemia;
(3) prevention of insulin overdosage leading to life-threatening
hypoglycemic shock (CNS disturbance due to lack of glucose).
Therapeutic principles. In healthy subjects, the amount of insulin is “automatically”
matched to carbohydrate intake, hence to blood glucose concentration.
The critical secretory stimulus is the rise in plasma glucose level. Food intake
and physical activity (increased glucose uptake into musculature, decreased
insulin demand) are accompanied by corresponding changes in insulin
secretion (A, left track). In the diabetic, insulin could be administered
as it is normally secreted; that is, injection of short-acting insulin
before each main meal plus bedtime administration of a Lente preparation to
avoid a nocturnal shortfall of insulin. This regimen requires a well-educated,
cooperative, and competent patient. In other cases, a fixed-dosage schedule
will be needed, e.g., morning and evening injections of a combination insulin
in constant respective dosage (A). To avoid hypo- or hyperglycemias with
this regimen, dietary carbohydrate (CH) intake must be synchronized with the
time course of insulin absorption from the s.c. depot. Caloric intake is to be distributed
(50% CH, 30% fat, 20% protein) in small meals over the day so as to
achieve a steady CH supply—snacks, late night meal. Rapidly absorbable CH
(sweets, cakes) must be avoided (hyperglycemic—peaks) and replaced with
slowly digestible ones. Acarbose (an !-glucosidase inhibitor)
delays intestinal formation of glucose from disaccharides.
Any change in eating and living habits can upset control of blood sugar:
skipping a meal or unusual physical stress leads to hypoglycemia; increased
CH intake provokes hyperglycemia.Hypoglycemia is heralded by
warning signs: tachycardia, unrest,tremor, pallor, profuse sweating. Some
of these are due to the release of glucose-mobilizing epinephrine. Countermeasures:
glucose administration, rapidly absorbed CH orally or 10–20 g glucose
i.v. in case of unconsciousness; if necessary, injection of glucagon, the
pancreatic hyperglycemic hormone. Even with optimal control of blood
sugar, s.c. administration of insulin cannot fully replicate the physiological situation.
In healthy subjects, absorbed glucose and insulin released from the
pancreas simultaneously reach the liver in high concentration, whereby effective
presystemic elimination of both substances is achieved. In the diabetic,
s.c. injected insulin is uniformly distributed in the body. Since insulin concentration
in blood supplying the liver cannot rise, less glucose is extracted from
portal blood. A significant amount of glucose enters extrahepatic tissues,
where it has to be utilized.

Treatment of Maturity-Onset (Type II) Diabetes Mellitus

In overweight adults, a diabetic metabolic condition may develop (type II or
non-insulin-dependent diabetes) when there is a relative insulin deficiency—
enhanced demand cannot be met by a diminishing insulin secretion. The
cause of increased insulin requirement is a loss of insulin receptors or an
impairment of the signal cascade activated by the insulin receptor. Accordingly,
insulin sensitivity of cells declines. This can be illustrated by comparing
concentration-binding curves in cells from normal and obese individuals
(A). In the obese, the maximum binding possible (plateau of curve) is displaced
downward, indicative of the reduction in receptor numbers. Also, at low insulin
concentrations, there is less binding of insulin, compared with the control condition.
For a given metabolic effect a certain number of receptors must be occupied.
As shown by the binding curves (dashed lines), this can still be achieved
with a reduced receptor number, although only at a higher concentration of
insulin. Development of adult diabetes
(B). Compared with a normal subject, the obese subject requires a continually
elevated output of insulin (orange curves) to avoid an excessive rise of
blood glucose levels (green curves) during a glucose load. When the secretory
capacity of the pancreas decreases, this is first noted as a rise in blood glucose
during glucose loading (latent diabetes). Subsequently, not even the fasting
blood level can be maintained (manifest, overt diabetes). A diabetic condition
has developed, although insulin release is not lower than that in a healthy
person (relative insulin deficiency).Treatment. Caloric restriction to
restore body weight to normal is associated with an increase in insulin receptor
number or cellular responsiveness. The releasable amount of insulin is
again adequate to maintain a normal metabolic rate.
Therapy of first choice is weight reduction, not administration of
drugs! Should the diabetic condition fail to resolve, consideration should first be
given to insulin replacement .

Oral antidiabetics of the sulfonylurea type increase the sensitivity of B-cells
towards glucose, enabling them to increase release of insulin. These drugs
probably promote depolarization of the !-cell membrane by closing off ATP-gated
K+ channels. Normally, these channels are closed when intracellular levels
of glucose, hence of ATP, increase. This drug class includes tolbutamide (500–
2000 mg/d) and glyburide (glibenclamide) (1.75–10.5 mg/d). In some patients,
it is not possible to stimulate insulin secretion from the outset; in others,
therapy fails later on. Matching dosage of the oral antidiabetic and caloric
intake follows the same principles as apply to insulin. Hypoglycemia is the
most important unwanted effect. Enhancement of the hypoglycemic effect
can result from drug interactions: displacement of antidiabetic drug from
plasma protein-binding sites by sulfonamides or acetylsalicylic acid.

Metformin, a biguanide derivative,
can lower excessive blood glucose levels, provided that insulin is present.
Metformin does not stimulate insulin release. Glucose release from the liver is
decreased, while peripheral uptake is enhanced. The danger of hypoglycemia
apparently is not increased. Frequent adverse effects include: anorexia, nausea,
and diarrhea. Overproduction of lactic acid (lactate acidosis, lethality 50%) is
a rare, potentially fatal reaction. Metformin is used in combination with sulfonylureas
or by itself. It is contraindicated in renal insufficiency and should therefore
be avoided in elderly patients. Thiazolidinediones (Glitazones: rosiglitazone,
pioglitazone) are insulinsensitizing agents that augment tissue
responsiveness by promoting the synthesis or the availability of plasmalemmal
glucose transporters via activation of a transcription factor (peroxisome
proliferator-activated receptor-").

Drugs for Maintaining Calcium
Homeostasis At rest, the intracellular concentration
of free calcium ions (Ca2+) is kept at 0.1 μM (see p. 128 for mechanisms involved).
During excitation, a transient rise of up to 10 μM elicits contraction in
muscle cells (electromechanical coupling) and secretion in glandular cells
(electrosecretory coupling). The cellular content of Ca2+ is in equilibrium with
the extracellular Ca2+ concentration (approx. 1000 μM), as is the plasma protein-
bound fraction of calcium in blood. Ca2+ may crystallize with phosphate to
form hydroxyapatite, the mineral of bone. Osteoclasts are phagocytes that
mobilize Ca2+ by resorption of bone. Slight changes in extracellular Ca2+ concentration
can alter organ function: thus, excitability of skeletal muscle increases
markedly as Ca2+ is lowered (e.g., in hyperventilation tetany). Three
hormones are available to the body for maintaining a constant extracellular
Ca2+ concentration. Vitamin D hormone is derived
from vitamin D (cholecalciferol). Vitamin D can also be produced in the body; it is
formed in the skin from dehydrocholesterol during irradiation with UV light.
When there is lack of solar radiation, dietary intake becomes essential, cod
liver oil being a rich source. Metabolically active vitamin D hormone results
from two successive hydroxylations: in the liver at position 25 (! calcifediol)
and in the kidney at position 1 (!calcitriol = vit. D hormone). 1-Hydroxylation
depends on the level of calcium homeostasis and is stimulated by parathormone
and a fall in plasma levels of Ca2+ or phosphate. Vit. D hormone promotes
enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of
the increased Ca2+ and phosphate concentration in blood, there is an increased
tendency for these ions to be deposited in bone in the form of hydroxyapatite
crystals. In vit. D deficiency, bone mineralization is inadequate
(rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vit. D is
given; in liver disease calcifediol may be indicated, in renal disease calcitriol. Effectiveness,
as well as rate of onset and cessation of action, increase in the order vit. D. <>