Burning epigastric pain exacerbated by fasting and improved with meals is a symptom complex associated with peptic ulcer disease (PUD). An ulcer is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation. Ulcers occur within the stomach and/or duodenum and are often chronic in nature. Acid peptic disorders are very common in the United States, with 4 million individuals (new cases and recurrences) affected per year.
Lifetime prevalence of PUD in the United States is ~12% in men and 10% in women. Moreover, an estimated 15,000 deaths per year occur as a consequence of complicated PUD. The financial impact of these common disorders has been substantial, with an estimated burden on direct and indirect health care costs of ~$10 billion per year in the United States.
The gastric epithelial lining consists of rugae that contain microscopic gastric pits, each branching into four or five gastric glands made up of highly specialized epithelial cells. The makeup of gastric glands varies with their anatomic location. Glands within the gastric cardia comprise <5% of the gastric gland area and contain mucous and endocrine cells. The majority of gastric glands (75%) are found within the oxyntic mucosa and contain mucous neck, parietal, chief, endocrine, and enterochromaffin cells. Pyloric glands contain mucous and endocrine cells (including gastrin cells) and are found in the antrum.
The parietal cell, also known as the oxyntic cell, is usually found in the neck, or isthmus, or the oxyntic gland. The resting, or unstimulated, parietal cell has prominent cytoplasmic tubulovesicles and intracellular canaliculi containing short microvilli along its apical surface. H+, K+-ATPase is expressed in the tubulovesicle membrane; upon cell stimulation, this membrane, along with apical membranes, transforms into a dense network of apical intracellular canaliculi containing long microvilli. Acid secretion, a process requiring high energy, occurs at the apical canalicular surface. Numerous mitochondria (30 to 40% of total cell volume) generate the energy required for secretion.
Hydrochloric acid and pepsinogen are the two principal gastric secretory products capable of inducing mucosal injury. Acid
secretion should be viewed as occurring under basal and stimulated conditions. Basal acid production occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours. Cholinergic input via the vagus nerve and histaminergic input from local gastric sources are the principal contributors to basal acid secretion. Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates (cephalic, gastric and intestinal).
Sight, smell, and taste of food are the components of the cephalic phase, which stimulates gastric secretion via the vagus nerve. The gastric phase is activated once food enters the stomach. This component of secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn activates the parietal cell via direct and indirect mechanisms. Distention of the stomach wall also leads to gastrin release and acid production.
The last phase of gastric acid secretion is initiated as food enters the intestine and is mediated by luminal distention and nutrient assimilation. A series of pathways that inhibit gastric acid production are also set into motion during these phases. The gastrointestinal hormone somatostatin is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl.
Somatostatin can inhibit acid production by both direct (parietal cell) and indirect mechanisms [decreased histamine release from enterochromaffin-like (ECL) cells and gastrin release from G cells. Additional neural (central and peripheral) and hormonal (secretin, cholecystokinin) factors play a role in counterbalancing acid secretion. Under physiologic circumstances, these phases are occurring simultaneously.
The acid-secreting parietal cell is located in the oxyntic gland, adjacent to other cellular elements ( ECL1 cell, D cell) important in the gastric secretory process. This unique cell also secretes intrinsic factor (IF). The parietal cell expresses receptors for several stimulants of acid secretion including histamine (H 2), gastrin (cholecystokinin B/gastrin receptor), and acetylcholine (muscarinic, M 3). Each of these are G protein-linked, seven transmembrane-spanning receptors.
Binding of histamine to the H2 receptor leads to activation of adenylate cyclase and an increase in cyclic AMP. Activation of the gastrin and muscarinic receptors results in activation of the protein kinase C/phosphoinositide signaling pathway. Each of these signaling pathways in turn regulates a series of downstream kinase cascades, which control the acid-secreting pump, H+, K+-ATPase. The discovery that different ligands and their corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid secretion that occurs when histamine and gastrin or acetylcholine are combined. More importantly, this observation explains why blocking one receptor type (H 2) decreases acid secretion stimulated by agents that activate a different pathway (gastrin, acetylcholine).
Parietal cells also express receptors for ligands that inhibit acid production (prostaglandins, somatostatin, and EGF2). The enzyme H+, K+-ATPase is responsible for generating the large concentration of H +. It is a membrane-bound protein that consists of two subunits, a and ß. The active catalytic site is found within the a subunit; the function of the ß subunit is unclear. This enzyme uses the chemical energy of ATP to transfer H + ions from parietal cell cytoplasm to the secretory canaliculi in exchange for K +. The H+,K+-ATPase is located within the secretory canaliculus and in nonsecretory cytoplasmic tubulovesicles. The tubulovesicles are impermeable to K +, which leads to an inactive pump in this location. The distribution of pumps between the nonsecretory vesicles and the secretory canaliculus varies according to parietal cell activity. Under resting conditions, only 5% of pumps are within the secretory canaliculus, whereas upon parietal cell stimulation, tubulovesicles are immediately transferred to the secretory canalicular membrane, where 60 to 70% of the pumps are activated. Proton pumps are recycled back to the inactive state in cytoplasmic vesicles once parietal cell activation ceases.
The chief cell, found primarily in the gastric fundus, synthesizes and secretes pepsinogen, the inactive precursor of the proteolytic enzyme pepsin. The acid environment within the stomach leads to cleavage of the inactive precursor to pepsin and provides the low pH (<2.0) required for pepsin activity. Pepsin activity is significantly diminished at a pH of 4 and irreversibly inactivated and denatured at a pH of =7. Many of the secretagogues that stimulate acid secretion also stimulate pepsinogen release. The precise role of pepsin in the pathogenesis of PUD3 remains to be established.
The SA node is normally the dominant cardiac pacemaker because its intrinsic discharge rate is the highest of all potential cardiac pacemakers. Its responsiveness to alterations in autonomic nervous system tone is responsible for the normal acceleration of heart rate during exercise and the slowing that occurs during rest and sleep. Increases in sinus rate normally result from an increase in parasympathetic tone acting via muscarinic receptors and/or an increase in sympathetic tone acting via ß-adrenergic receptors.
Slowing of the heart rate is normally due to opposite alterations. In adults, the normal sinus rate under basal conditions is 60 to 100
beats/min. Sinus bradycardia is said to exist when the sinus rate is <60 beats/min, and sinus tachycardia when it is >100 beats/min.
However, there is wide variation among individuals, and rates <60 beats/min do not necessarily indicate pathologic states. For example, trained athletes often exhibit resting rates <50 beats/min due to increases in vagal tone. Normal elderly individuals may also show marked sinus bradycardia at rest.
In patients with idiopathic PAN, glucocorticoids and cytotoxic agents remain the cornerstones of treatment. Approximately half of patients with PAN achieve remissions or cures with high doses of glucocorticoids alone. Cyclophosphamide (eg, 2 mg/kg/d orally or 0.6 g/m2/mo intravenously, decreased in the setting of renal dysfunction) is indicated for patients whose disease is refractory to corticosteroids or who have serious involvement of major organs. Prophylaxis against Pneumocystis jiroveci pneumonia is an important consideration in patients treated with these medications.
Treatment of HBV-associated PAN with immunosuppressive agents has deleterious long-term effects on the liver. Fortunately, the availability of effective antiviral agents has revolutionized the treatment of HBV-associated cases in recent years. One effective strategy involves the initial use of prednisone (1 mg/kg/d) to suppress the inflammation. Patients begin 6-week courses of plasma exchange (approximately three exchanges per week) simultaneously with the start of prednisone. The doses of glucocorticoids are tapered rapidly (over approximately 2 weeks), followed by the initiation of antiviral therapy (eg, lamivudine 100 mg/d).
Even when flagrant inflammation is present, PAN may elude diagnosis for weeks or months. Except for evidence obtained from angiography or biopsy, the disease has no individual features that are pathognomonic. Many connective tissue diseases must be considered in the differential diagnosis of PAN. However, systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disorders usually can be distinguished from PAN by the presence of autoantibodies (eg, anti-Ro/SS-A, anti-La/SS-B, anti-Sm, anti-RNP). These are absent in PAN.
In its early phases, rheumatoid arthritis may mimic PAN, but the arthritis of PAN is usually migratory and always nondestructive. Similarly, although the fever pattern of PAN may recall Still disease, the evanescent, salmon-colored rash in that disorder is atypical of PAN. Moreover, diffuse polyarthritis develops in 95% of patients with Still disease within 1 year (or earlier) of disease onset. The catastrophic antiphospholipid syndrome, which causes digital ischemia, strokes, and other arterial thrombotic events, may be confused with PAN. However, venous events, which are even more common than arterial events in most patients with the antiphospholipid syndrome, are not characteristic of PAN.
The lack of pulmonary involvement in PAN helps distinguish it from most cases of ANCA-associated vasculitis. The occurrence of pulmonary lesions (pulmonary nodules, cavities, infiltrates, or alveolar hemorrhage) in combination with systemic vasculitis shifts the differential diagnosis in favor of other vasculitides, such as Wegener granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. In addition, features of small-vessel disease (eg, purpura) are absent in PAN. Isolated peripheral nervous system vasculitis, a form of vasculitis that involves the peripheral nervous system alone, may mimic PAN and require similar therapy. In addition, in a subset of cases, the predominant features of PAN imitate the presentation of giant cell arteritis (eg, headache, jaw claudication, fever, and polymyalgias). Findings of histopathologic features of PAN on temporal artery biopsy specimens have been reported.
The multiorgan system inflammatory nature of PAN may be mimicked by numerous bacterial, mycobacterial, or fungal infections. These must be excluded with great caution before beginning a treatment course for vasculitis. Finally, a host of other systemic or single-organ diseases may mimic PAN in their individual organ features. These include inflammatory bowel disease, sarcoidosis, erythema nodosum, atrophie blanche (livedoid vasculitis), cholesterol emboli, fibromuscular dysplasia, and malignancies (particularly lymphoma). PAN may occur as a complication of hairy cell leukemia.
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Symptoms and Signs
PAN can involve virtually any organ system, with the exception of the lungs. The disease, however, demonstrates a predilection for certain organs, particularly the skin, peripheral nerves, gastrointestinal tract, and kidneys. A nearly universal complaint among patients is pain caused by myalgias, arthritis, peripheral nerve infarction, testicular ischemia, or mesenteric vasculitis.
Fevers are a common feature of PAN. The characteristics of the fever vary substantially among patients, ranging from periods of low-grade temperature elevation to spiking febrile episodes accompanied by chills. Malaise, weight loss, and myalgias are also common in PAN.
Skin and Joints
Vasculitis of medium-size arteries may produce several types of skin lesions. These cutaneous findings include livedo reticularis, nodules, papules, ulcerations, and digital ischemia leading to gangrene. All of these findings or combinations of them may occur in the same patient. The livedo reticularis, which may have a diffuse distribution over the extremities and buttocks, does not blanch with the application of pressure to the skin. Nodules, papules, and ulcers tend to occur on the lower extremities, particularly near the malleoli, in the fleshy parts of the calf, and over the dorsal surfaces of the feet. Nodules frequently evolve into ulcerations that have scalloped borders. Digital ischemia, often accompanied by splinter hemorrhages, sometimes leads to tissue loss. Arthralgias of large joints (knees, ankles, elbows, wrists) occur in up to 50% of patients; however, true synovitis is seen in many fewer patients.
Mononeuritis multiplex, the infarction of named nerves by inflammation in the vasa nervorum, occurs in approximately 60% of patients with PAN. The most commonly involved nerves are the sural, peroneal, radial, and ulnar. Vasculitic neuropathy tends to involve the longest (ie, distal) nerves first and usually begins asymmetrically. Thus, the first motor symptoms of vasculitic neuropathy may be a foot or wrist drop (resulting from infarctions of the peroneal and radial nerves, respectively). In advanced stages, the neuropathy may mimic a confluent, symmetric polyneuropathy. Careful history taking, however, may unmask its initial asymmetry.
The gastrointestinal manifestations of PAN occur in approximately half of all patients and are among the most challenging symptoms to diagnose correctly because of their nonspecific nature. Postprandial abdominal pain (“intestinal angina”) is common. Involvement of the mesenteric arteries in PAN may lead to the disastrous complications of mesenteric infarction or aneurysmal rupture, each of which is associated with high mortality rates. Angiography of the mesenteric vessels reveals multiple microaneurysms. These range in size from lesions that are barely visible to the naked eye to those large enough to rupture. Sometimes PAN is detected at cholecystectomy or appendectomy in the absence of other disease manifestations. In such cases, surgical removal of the involved organ may be curative.
Intraparenchymal Renal Inflammation
This major feature of PAN is found in 40% of patients. The inflammatory process targets the renal and interlobar arteries (the medium-size, muscular arteries within the kidney) and occasionally also involves the smaller arcuate and interlobular arteries. Angiography may reveal microaneurysms within the kidney or large, wedge-shaped renal infarctions. Red blood cell casts on urinalysis imply glomerulonephritis and thus usually implicate another disease (eg, microscopic polyangiitis). However, both proteinuria and hematuria may be observed in PAN.
Patchy necrosis of the myocardium caused by subclinical arteriolar involvement is a frequent finding. Tachycardia is common, either as a manifestation of direct cardiac involvement or a reflection of the general inflammatory state. Congestive heart failure and myocardial infarction sometimes occur. Specific heart lesions are rarely diagnosed while the patient is alive; however, autopsy series indicate that cardiac involvement is present in a majority of patients with PAN.
Central nervous system involvement occurs in a small percentage of patients with PAN. The usual presentations are encephalopathy and strokes. Renin-mediated hypertension may contribute to both of these neurologic complications. Other unusual presentations of PAN include involvement of the eyes (scleritis), pancreas, testicles, ureters, breasts, and ovaries.
Although the laboratory features of PAN are often strikingly abnormal and help characterize the disease process as inflammatory, they do not distinguish PAN from a host of other inflammatory diseases. Anemia, thrombocytosis, and elevation of acute phase reactants are typical. Erythrocyte sedimentation rate and C-reactive protein are often useful in longitudinal evaluations of disease activity but are imperfect for this purpose. Assays for antinuclear antibodies and rheumatoid factor are also generally negative in patients with PAN, but low titers of these antibodies are detected in a few patients. Patients with HBV-associated PAN are generally hypocomplementemic, regardless of whether they have demonstrable cryoglobulins. When associated with HBV, PAN usually develops within weeks to months of the acute viral infection.
When tested by immunofluorescence, the sera of some patients with PAN are positive for antineutrophil cytoplasmic antibodies (ANCAs). However, specific enzyme immunoassays for antibodies to proteinase-3 or myeloperoxidase (the two antigens known to be associated with systemic vasculitis) are negative. Thus, PAN is not considered to be an ANCA-associated vasculitis.
The diagnosis of PAN requires either a tissue biopsy or an angiogram that demonstrates microaneurysms.
In the skin, medium-size arteries lie within the deep dermis and in the subdermal adipose tissue. Thus, the diagnosis of PAN can be made by obtaining biopsy specimens of the skin that capture lobules of subcutaneous fat. Biopsies of nodules, papules, and ulcer edges have higher yields than biopsies of livedo reticularis. Nerve conduction studies are useful in detecting the typical axonal pattern of nerve injury and identifying involved nerves for biopsy. Because muscle tissue is highly vascular and may harbor involved vessels even in the absence of symptoms or signs of muscle involvement, biopsies of adjacent muscle should be performed simultaneously (eg, the gastrocnemius, if the sural nerve is biopsied). Blind biopsies of asymptomatic organs such as the testicle, however, are rarely diagnostic.
PAN is a panarteritis characterized by transmural necrosis and a homogeneous, eosinophilic appearance of the blood vessel wall (fibrinoid necrosis). The cellular infiltrate is pleomorphic, with both polymorphonuclear cells and lymphocytes present in varying degrees at different stages. Degranulation of neutrophils within and around the arterial wall leads to leukocytoclasis. The vascular wall inflammation in PAN may be strikingly segmental, affecting only part of the circumference of a given artery. Segmental necrosis, in turn, leads to aneurysm formation. During later stages, complete occlusion may occur secondary to endothelial proliferation and thrombosis. Throughout involved tissues, the coexistence of acute and healed lesions is typical. Even in patients without gastrointestinal symptoms, mesenteric angiography may demonstrate telltale microaneurysms.
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Essential of diagnosis on Polyarteritis Nodosa
- Subacute onset of constitutional complaints (eg, fever, weight loss, malaise, arthralgias), lower extremity nodules and ulcerations, mononeuritis multiplex, and intestinal angina (postprandial pain caused by the involvement of mesenteric vessels).
- Angiogram or biopsy of an involved organ required for diagnosis.
- Angiography may reveal microaneurysms in the kidneys or gastrointestinal tract.
- Biopsies of the skin and peripheral nerves (with sampling of the adjacent muscle) are the least invasive ways of confirming the diagnosis histopathologically.
General Consideration on Polyarteritis Nodosa
Classic polyarteritis nodosa (PAN), as defined by a 1994 Consensus Conference, is a disorder characterized by necrotizing inflammation of small or medium arteries that spares the smallest blood vessels (eg, arterioles or capillaries) and is not associated with glomerulonephritis. Additional distinguishing features of PAN include the confinement of the disease to the arterial circulation (as opposed to the venous) and the absence of granulomatous inflammation.
Reported annual incidence rates of PAN range from 2 to 9 cases per million people per year. A higher incidence (77 cases/million) was reported in an Alaskan area hyperendemic for hepatitis B virus (HBV). With the availability of the HBV vaccine, however, the percentage of cases associated with HBV has declined substantially (now < 10% of all cases in the developed world). PAN appears to affect men and women with approximately equal frequencies and to occur in all ethnic groups.
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Location is crucial in both benign and malignant tumors. A small (1-cm) pituitary adenoma can compress and destroy the surrounding normal gland and give rise to hypopituitarism. A 0.5-cm leiomyoma in the wall of the renal artery may lead to renal ischemia and serious hypertension. A comparably small carcinoma within the common bile duct may induce fatal biliary tract obstruction.
Hormone production is seen with benign and malignant neoplasms arising in endocrine glands. Adenomas and carcinomas arising in the β-cells of the islets of the pancreas can produce hyperinsulinism, sometimes fatal. Analogously, some adenomas and carcinomas of the adrenal cortex elaborate corticosteroids that affect the patient (e.g., aldosterone, which induces sodium retention, hypertension, and hypokalemia). Such hormonal activity is more likely with a well-differentiated benign tumor than with a corresponding carcinoma.
A tumor may ulcerate through a surface, with consequent bleeding or secondary infection. Benign or malignant neoplasms that protrude into the gut lumen may become caught in the peristaltic pull of the gut, causing intussusception and intestinal obstruction or infarction.
This is an autosomal dominant disorder in which patients develop a range of tumors, most commonly bilateral vestibular (acoustic) schwannomas and multiple meningiomas. Gliomas, typically ependymomas of the spinal cord, also occur in these patients. Individuals with NF2 may also have non-neoplastic lesions within the nervous system where Schwann cells or glial cells are present in small collections in inappropriate places.
This disorder is much less common than NF1, having a frequency of 1 in 40,000 to 50,000. Unlike NF1, in NF2 there is some correlation between the type of mutation and clinical symptoms, with nonsense mutations usu-ally causing a more severe phenotype than missense mutations. As mentioned previously, the NF2 gene is commonly mutated in sporadic meningiomas and schwannomas as well.