The enlargement of an organ or tissue because of an abnormal increase in the number of cells

Hypertrophy

The consistent observation of renal, and in particular glomerular, hypertrophy after renal mass reduction has prompted investigators to propose that processes involved in, or resulting from, hypertrophy may contribute to progressive renal injury in CKD.538 The well- documented observation that renal and glomerular hypertrophy precede the development of diabetic nephropathy and the finding of a positive association between glomerular size and early sclerosis in rats subjected to renal mass ablation539 further suggests that hypertrophy may play a direct role in the pathogenesis of glomerulosclerosis. Several clinical observations have also supported an association between glomerular hypertrophy and renal injury. Oligomeganephronia, a rare congenital condition with a nephron number 25% of normal or less, is characterized by marked hypertrophy of the remaining glomeruli and the development of proteinuria and renal failure in adolescence, with FSGS as the typical renal biopsy finding.540 In children with minimal change disease, a glomerulopathy generally associated with spontaneous remission and lack of progression to renal failure, investigators have noted an association between glomerular size and the risk of developing FSGS and renal failure.541

Several interventions have been used in experiments to interrupt the development of glomerular hypertrophy after renal mass reduction and thereby assess its role in renal disease progression, but have produced contradictory results. Rats subjected to 5/6 nephrectomy were compared with rats in which 2/3 of the left kidney was infarcted and the right ureter drained into the peritoneal cavity, an intervention that apparently results in decreased renal clearance without compensatory renal hypertrophy.538 Micropuncture studies confirmed similar degrees of elevation of PGC and SNGFR in both models. At 4 weeks, however, the maximal planar area of the glomerulus was significantly less, and glomerular injury, as assessed by sclerosis index, was significantly reduced in ureteroperitoneostomized rats versus 5/6 nephrectomized controls. Accordingly, the authors have concluded that glomerular hypertrophy is more important than glomerular capillary hypertension in the progression of glomerular injury in this model.

Dietary sodium restriction has also been used to inhibit renal hypertrophy after 5/6 nephrectomy. Although sodium restriction had no effect on glomerular hemodynamics, glomerular volume was significantly reduced in 5/6 nephrectomized rats fed low versus normal sodium diets.134 Moreover, urinary protein excretion was lower, and glomerulosclerosis was less severe, in rats on restricted sodium intake. These findings were extended by another study in which the effect of sodium restriction in preventing glomerular hypertrophy and ameliorating glomerular injury was confirmed, but which also found that these benefits were overcome by the administration of an androgen that stimulated glomerular hypertrophy, despite sodium restriction. Glomerular hemodynamics were similar among the groups.542 On the other hand, treatment with seliciclib, a cyclin-dependent kinase inhibitor, reduced renal hypertrophy by 45% after 5/6 nephrectomy but had no effect on kidney damage.543

Hypertrophy

Hypertrophy is defined as an increase in tissue mass because of an increase in cell size. It is most commonly encountered as hypertrophy of the retinal pigment epithelium (RPE) subsequent to retinal detachment of more than a few hours' duration. It is a rapid, reliable, and more or less specific change that allows one to separate genuine detachment from artifact (Figure 4-1). Hypertrophy is also seen in many other ocular tissues as a prelude to replication, such as occurs with hypertrophy of iris endothelium preparatory to the development of a preiridal fibrovascular membrane, hypertrophy of corneal stromal fibroblasts in the early stages of stromal repair, and hypertrophy of lens epithelium at various stages of cataract formation.

Surgical Excision

Therapy of keloids limited to traditional surgical excision with primary closure leads to a recurrence rate of greater than 50%. Mixing corticosteroids with the local anesthetic at the time of surgical removal provides superior results. In treating recalcitrant keloids over 1 to 1.5 cm, the best surgical results have been obtained using intralesional corticosteroid injections of triamcinolone (diluted to 2.5 to 5.0 mg/mL) into the immediate subcutaneous interface of the keloid and normal deep skin structures. The steroid injections can be administered 3 months and 6 weeks before scheduled surgical excision and again on the day of skin surgery immediately before the procedure. Follow-up at 4 and 8 weeks after surgery is important to detect any recurrence, which can be aborted with further injections. For smaller lesions, many clinicians will just inject at the time of surgery.

Proper surgical technique during the excision reduces the recurrence of keloids. Because tissue trauma may incite excessive growth, the wound bed and surrounding tissues must be handled gently. Avoid the use of instruments that crush tissue as well as overly aggressive cautery. Superpulse carbon dioxide lasers allow precise excision and cautery and cause minimal thermal damage to surrounding tissue. This, despite their relative expense, makes them useful in excising some keloids. Radiofrequency surgery has similar results (seeChapter 25, Radiofrequency Surgery [Modern Electrosurgery]).

When an excision is performed, close the skin under minimal tension. Consider gentle undermining to decrease wound tension. Some surgeons avoid subcuticular absorbable sutures, which may increase tissue reaction. Skin closure should be accomplished with a very fine nonabsorbable suture material, such as 6-0 nylon. Topical adhesives (“tissue glues” such as Dermabond, SurgiSeal, Histoacryl Blue, or Periacryl) and wound closure strips help to close the wound with the least possible trauma and reduce tension on wound edges. They may also reduce the total number of sutures needed.

Some surgeons advocate removal of every vestige of a keloid; however, wide excision of normal skin around keloids does not reduce the rate of recurrence. Others advocate leaving a rim of incompletely excised keloid in place to serve as a barrier to further keloid growth. It is unclear whether this technique provides significant benefit over standard excision.

Local advancement flaps can be used to limit the wound tension after excision.Fig. 28.1 shows a low-tension flap created after the removal of a globular earlobe keloid. Although some practitioners advocate skin grafting to provide low-tension skin closure, large donor-site keloids can also develop. Advanced closure techniques such as rotation advancement or M-plasty to cover large areas of keloid removal may be indicated to minimize tension on skin edge closure.

Evidence suggests that the use of Silastic-silicone preparations (e.g., Mederma, ReJuveness, Biodermis, Mepiform, Kelo-cote) immediately after surgery may reduce the occurrence of keloids in those prone to excessive scarring.

3. Mitochondria

Hypertrophy of mitochondria, termed megamitochondria, may be induced by a variety of chemicals, including cuprizone, ethionine and orotic acid. In the case of cuprizone and isonicotinic acid derivatives, large mitochondria result from the fusion of preexisting ones. Mitochondrial hypertrophy is not discernible by light microscopy. By electron microscopy, hypertrophic mitochondria have normal cristae and normal matrix density. This should be distinguished from swollen mitochondria, which have swollen cristae and irregular densities in the matrix. Mitochondrial hypertrophy and swelling have also been distinguished biochemically.

Mitochondrial swelling is associated with uncoupling of oxidative phosphorylation, whereas mitochondrial hypertrophy is associated with normal oxidative phosphorylation.

Low Vaginal Confluence: Clitoral Hypertrophy

The vast majority of children who undergo surgery for DSD or urogenital sinus conditions have a low vaginal confluence amenable to flap vaginoplasty. They usually have clitoral hypertrophy. As noted earlier, the decision to perform clitoroplasty is very controversial in infants, but the techniques are applicable to any age. This decision should only be made after careful consideration and explanation to the patient/family of all pros, cons, risks, benefits, and controversies. Clitoroplasty and classic flap vaginoplasty are described. With the child in the supine position, a traction suture is placed through the glans, and the proposed incisions are outlined with a skin scribe. Along these lines, 0.5% lidocaine with 1 : 200,000 epinephrine is injected subcutaneously for hemostasis. The proposed incision around the glans, leaving the inner surface of the prepuce intact, is drawn along with parallel longitudinal lines on either side of the ventral mucosal strip (urethral plate equivalent) extending around the meatus. A perineal omega-shaped flap with the apex near the meatus is outlined. AY-shaped incision line is drawn around the inferior aspect of each labia majora. The incision begins on the dorsal aspect of the clitoris, and all inner preputial skin is left intact for later construction of a clitoral hood. This skin has been shown to be second only to the glans in sensitivity (Schober and Ransley, 2002). The clitoris is degloved while keeping the ventral “urethral plate” intact with the meatus. Dissection is carried out to the level of the bifurcation of the corporeal bodies ventrally and the pubis dorsally, and care should be taken to not injure any neurovascular tissue (seeFig. 49.12). It is important to recognize that the clitoral arterial supply branches from the internal pudendal artery from Alcock's canal near the ischial tuberosity. These arteries course ventrally and are on the medial aspect of the bifurcated corpora, where they then course dorsally along the phallic shaft (Schnitzer and Donahoe, 2001). The clitoral neural bundles ascend along the ischiopubic rami and meet as paired bundles that pass along the dorsal surface and then pass largely intact into the glans (Baskin et al., 1999;O'Connell et al., 2005). My current clitoroplasty technique, regardless of patient age, is described, but, regardless of technique, the just-described clitoral innervation must not be disturbed.

A tourniquet may be placed at the base of the clitoris, or the bifurcated corpora may be compressed against the pubis with Kitner dissectors. Longitudinal incisions are then made through the Buck fascia on the ventralmost aspect of each corporeal body (Fig. 49.15); the incisions extend from the glans to the bifurcation to expose the corpora cavernosa tissue, which is dissected (often teased) from the tunics. The tunics are left undisturbed, except for the ventral incision.No tunical tissue is excised. The dorsal neurovascular bundle should not be mobilized or disturbed in any way. The proximal ends of the erectile tissue only are suture ligated. Other techniques involve mobilization of the neurovascular bundles from the corpora, but I believe this is more likely to injure clitoral sensitivity and vascularity. If mobilization is done,Braga and Salle (2009) pointed out the need to dissect in the exact plane (below the second layer of the Buck fascia just beneath the tunica albuginea) to avoid neurovascular injury. Efforts to decrease the size of the glans are controversial and, if attempted, should be done with great caution. Studies byJuskiewenski et al. (1982) andBaskin et al. (1999) suggest that any glans excision should be performed ventrally near the midline (similar to hypospadias glans wings). The glans is innervated by perforating branches entering at the dorsal junction of the glans and corpora (Baskin et al., 1999). Excision of glanular epithelium to conceal the glans is to be avoided because the sensory neuropeptides are located just beneath this layer.Remember there are no data to suggest that a large glans or clitoris is detrimental to sexual function. The glans is now secured to the coronal stumps. In my experience, a glans sewn to the pubis results in an abnormally high prominent position (Rink and Yerkes, 2001).Pippi Salle et al. (2007) described an alternative technique whereby the corpora are dissected from the neurovascular bundle, separated, and buried beneath the labia, which allows reversibility of the clitoroplasty in those patients with later gender dysphoria.

Athlete’s Heart

Physiologic hypertrophy and cavity enlargement are the heart’s normal adaptation to rigorous athletic training. When remodeling is move vigorous, athlete’s heart can be hard to distinguish from modest levels of pathological hypertrophy. In addition to a recent history of intense physical training and a high exercise capacity, features favoring athlete’s heart are male gender, concomitant enlargement of heart chambers, concentric hypertrophy, absence of left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve, normal diastolic parameters, and absence of repolarization abnormalities in the ECG. The degree of hypertrophy that results from athletic training is also typically modest, most commonly 12–13 mm; rarely up to 16 mm. More extreme amounts of LVH should raise suspicion for pathological hypertrophy. Detraining for 3–6 months can be attempted to differentiate pathologic hypertrophy from physiologic hypertrophy in the athlete [15], as physiologic hypertrophy should regress.

Hypertrophy

Hypertrophy is an increase in the size of cells (or tissues) in response to various stimuli. A typical example is muscular hypertrophy in response to exercise. Exercise stimulates skeletal and cardiac muscle fibers to increase in diameter and to accumulate more structural contractile proteins. Hypertrophy may occur as a compensatory response to injury when parenchymal cells are damaged or lost. For instance, following myocardial infarction, cardiac myocytes cannot undergo hyperplasia to replace destroyed muscle fibers but residual myocytes enlarge (hypertrophy) in an attempt to replace some of the function of the lost myofibers (Fig. 1-10). Most forms of hypertrophy are actually far more complex than a simple increase in cell size (e.g., hypertrophy of cardiac myocytes is associated with changes in the pattern of gene expression that result in the reactivation of embryonic genes and alter the structure of contractile proteins and modify the density of hormone receptors). Physiologic hypertrophy is usually adaptive and improves function. Pathologic hypertrophy may be adaptive in some situations but often results in changes in gene expression that can exacerbate organ dysfunction.

Myocardial Hypertrophy.

See the discussion on hypertrophy in Chapter 1.

Hypertrophy of the myocardium represents an increase in muscle mass, which is the result of an increase in the size of cardiac muscle cells (Fig. 10-9; also see Fig. 10-5, B and E-Fig. 10-9). Two anatomic forms of hypertrophy are recognized. Eccentric hypertrophy results in a heart with enlarged ventricular chambers and walls of normal to somewhat decreased thickness. Volume-overload hypertrophy is characterized by new sarcomeres being assembled in series within sarcomeres resulting in increased length of myofibers. In concentric hypertrophy, the heart is characterized by small ventricular chambers and thick walls. Pressure-overload hypertrophy is the result of the formation of new sarcomeres assembled predominantly in parallel to the long axes of cells resulting in an increase in thickness of the myofiber. Some cats with hyperthyroidism have a cardiac hypertrophy that is mediated by enhanced production of myocardial contractile proteins under the influence of increased concentration of circulating thyroid hormones (Fig. 10-10). The hypertrophy is reversible on return to euthyroidism.

Three stages of myocardial hypertrophy are recognizable: (1) initiation, (2) stable hyperfunction, and (3) deterioration of function associated with degeneration of hypertrophied myocytes. Microscopically, in myocardial hypertrophy, the myocytes are enlarged and have large nuclei (Fig. 10-11).

Congenital hypertrophy of the retinal pigment epithelium

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) and CHRPE-like lesions may be confused with nevi, but are usually able to be distinguished on ophthalmoscopic examination. CHRPE are typically unilateral, darkly pigmented, round, well-circumscribed, flat lesions at the level of the RPE. They often have a surrounding pigmented or nonpigmented halo, or a double halo consisting of pigmented and nonpigmented rings. Intralesional lacunae are often present and may enlarge. CHRPE-like lesions, associated with familial adenomatous polyposis (FAP), are similar in appearance, but are bilateral, multiple, and pisciform in shape.95

Hypertrophic Gastritis

Hypertrophy of the fundic mucosa is uncommon and is often part of the breed-specific gastropathies or gastroenteropathies mentioned previously. Measurement of gastric pH and serum gastrin can help to differentiate idiopathic hypertrophic pylorogastropathy from hypertrophy associated with hypergastrinemia.25,26 Pancreatic polypeptide-producing tumors may also be associated with mucosal hypertrophy. Concurrent hypergastrinemia should prompt consideration of underlying hepatic or renal disease, achlorhydria, or gastrin-producing tumors, which should be pursued appropriately. Basenji gastroenteropathy is variably associated with fasting hypergastrinemia and exaggerated secretin-stimulated gastrin, and anecdotal reports suggest that affected Basenjis may respond to antimicrobial therapy. Brachycephalic, middle-aged, small-breed dogs such as Shih Tzus seem predisposed to the syndrome of hypertrophic pylorogastropathy, in which vomiting is secondary to pyloric outflow obstruction caused by hypertrophy of the pyloric mucosa and/or muscularis.20,21 Antral hypertrophy of brachycephalic dogs causes outflow obstruction and is treated surgically.

When hypertrophic gastropathy, ulcers or erosions, or excessive gastric juice are encountered at endoscopy, intravenous H2-antagonists or proton pump inhibitors can be given during the endoscopic procedure as prophylaxis for postoperative perforation or esophagitis.2