3 Nutritional Disorders

65 INFLAMMATORY BOWEL DISEASE

555.9

(Crohn’s Granulomatous Enterocolitis,

Regional Enteritis, Ulcerative Colitis)

F. Hampton Roy, MD, FACS

Little Rock, Arkansas

total colectomy is advised to remove intractable bowel or stop progression of liver disease.

Fistulas caused by Crohn’s disease usually require surgical removal, particularly when they have formed connections with the vagina, bladder, or urethra.

Both Crohn’s disease and ulcerative colitis are associated with increased risk of developing cancer, so patients require regular monitoring by means of office visits, interval histories, physical examinations, and radiocontrast and endoscopic examinations.

Neither Crohn’s disease nor ulcerative colitis has a clearly defined etiology that explains all cases. Multifactoral influences are being defined.

Genetic factors are clear to those who have seen enough patients and heard from patients about other family members with the same disorder. Parents and children, cousins, aunts, uncles and grandparents have had the same syndrome.

Several familial subgroups of Crohn’s disease have similar clinical presentations, symptoms, signs, and courses. The first subgroup involves oral and gastroduodenal-jejunal disorders. The second focuses around the ileocecal junction, with focal inflammation and obstructions. The third clustering affects the rectum and tends to produce fistulas.

Genetic anticipation occurs; the second generation is likely to be affected earlier than was the first generation. The children of a father with Crohn’s disease are more likely to be affected than are those whose mother has Crohn’s disease.

Allergic mechanisms in some patients explain exacerbations provoked by the ingestion of foods such as cow’s milk and milk products or of drugs. Smoking more than 10 cigarettes per day is associated with more severe Crohn’s disease.

Stress, either recent or chronic, is often associated with initial presentation or with exacerbations.

These disorders are characterized by both gastrointestinal and systemic symptoms and signs. Generalized malaise, fevers, arthralgia, anemia, erythema nodosum, pyoderma gangrenosum, large oral ulcers, weight loss, and growth delay are the systemic symptoms and signs. Elevated white blood cell (WBC) count and erythrocyte sedimentation rate are often present. Crampy abdominal pain, diarrhea with or without blood, excess mucus, and obstructions are the intestinal presentations.

Crohn’s disease, usually insidiously but occasionally acutely, produces focal inflammation at any point from mouth to anus, most commonly in the terminal ileum. Fistulas may form from bowel to bowel or bowel to vagina, skin, or bladder. Radiography can demonstrate the ‘string sign’ of narrowed lumen in the terminal ileum. Biopsies of ulcers reveal granulomatous inflammation with giant cells in 30% of cases.

Ulcerative colitis can have a chronic, indolent onset or a fulminant presentation with explosive diarrhea, fever, and systemic toxicity. Endoscopy reveals eroded, often hemorrhagic colonic mucosa. Biopsy and histopathology demonstrate acute inflammatory cells. Arthralgias and skin lesions are seen. Persistence of active disease can produce liver dysfunction, damage, and sclerotic cirrhosis. In patients with liver disease, colectomy stops progression of the hepatopathy.

Chronicity, remission, and recurrence are common to the clinical courses of both these disorders. Prognosis varies, in part related to genetic factors, which are currently being recognized and clarified. Some patients respond to medical regimens and experience long-lasting subsidence of symptoms and signs. Others respond and then, as drug dosages are reduced, find that symptoms and signs return. A small number of patients do not respond, and surgery is required to remove affected segments of the small or large bowel. In some cases of ulcerative colitis,

Treatment is difficult, primarily because etiologic mechanisms have not been defined. Family physicians, internists, gastroenterologists, and general surgeons, all with slightly different educations, experiences and psychologic natures, are the primary and secondary managers of these patients. In their desperation, patients often seek care from many different physicians. Ophthalmologists should not try to manage these patients alone but should work closely with other experienced practitioners.

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●Systemic corticosteroids are the most commonly used agents. They are familiar, available, standardized and effective. Initial high dosages rapidly reduce abdominal pain, nausea, fever and diarrhea. Gradual tapering over weeks to months often brings stability to patients.

●Sulfa-containing drugs such as sulfasalazine are used for chronic maintenance therapy.

●Metronidazole is another useful agent.

●Severe refractiveness to these therapies forces the use of cytotoxic agents such as azathioprine.

●General supportive measures such as liquid or low-residue diets, pain medication and antispasmodic drugs give relief.

●Oral multivitamin use is important.

Surgical intervention is indicated as mentioned above. In some instances, removal of affected bowel is followed by a general systemic improvement, implying that something toxic in the gut has had a systemic effect.

COMPLICATIONS

Ocular complications occur in about 10% of patients with Crohn’s disease and less frequently in patients with ulcerative colitis. Ocular problems may present before a gastrointestinal diagnosis is made. Crohn’s disease begins with episcleritis, the most common symptom, and a peculiar subepithelial keratopathy, the most specific. Limbal corneal infiltrates, iritis, iridocyclitis, macular edema, retinal vasculitis, papillitis, choroiditis, and orbital myositis are primary complications. Ulcerative colitis seems to have iritis or iridocyclitis as its major ocular complication.

Ocular complications can be divided into three groups:

Primary

Primary complications associated with the activity of Crohn’s disease occur frequently and respond to systemic therapy, such as systemic corticosteroids or surgical excision. The primary complications of Crohn’s disease include specific epithelial and anterior stromal keratopathy, limbal corneal infiltrates, subconjunctival hemorrhage, episcleritis, scleritis, acute iritis, chronic iridocyclitis, macular edema, retinal vasculitis, and papillitis. Orbital inflammation can produce proptosis, pain, and limited movement caused by myositis or general inflammation. Optic neuritis or chiasmal involvement can cause the loss of vision in one or both eyes. Episcleritis has been, in the author’s experience, the most common ocular complication of Crohn’s disease; thus, it is a diagnostic point in the differentiation of Crohn’s from ulcerative colitis and an indicator of the activity of the basic disease.

Secondary

Secondary complications of Crohn’s disease include night blindness and dry eyes caused by vitamin A deficiency induced by patients’ reduced intake of vegetables, which irritate the gut, and by an absent or a diseased ileum that prevents the normal absorption of vitamins. Refraction changes occur when patients start or stop taking systemic corticosteroids. Cataracts occur after the prolonged use of corticosteroids or because of chronic iridocyclitis. Exudative retinal detachment has been seen in two patients. Only after drainage of a psoas abscess did one patient improve. The other patient had posterior scleritis that improved with systemic corticosteroids. Optic disk edema occurred in two patients, presumably from posterior scleritis.

Scleromalacia caused by scleritis occurred in one patient, and Candida endophthalmitis caused by intravenous nutrition occurred in another.

Coincidental

Coincidental complications occur so frequently that they are considered not related. They can include conjunctivitis, recurrent corneal erosion, glaucoma, and generalized retinal artery narrowing. Ulcerative colitis is complicated in the eyes by iritis and iridocyclitis.

MANAGEMENT

Treatment of ocular complications begins with identification of the type of complication. Primary complications require attention to the intestinal disease and clarification of its status. More aggressive treatment, either medically or surgically, may be indicated.

●Acute iritis requires topical corticosteroids, cycloplegics, and, at times, systemic corticosteroids.

●Limbal corneal infiltrates and episcleritis commonly respond to topical steroids.

●Chronic iridocyclitis is closely associated with active gut disease and has responded to excision of involved intestinal tissue. Systemic corticosteroids given for both conditions help but are not curative.

●The characteristic keratopathy of Crohn’s disease does not impair vision and is not painful, so it requires no therapy.

●Macular edema syndromes usually respond to systemic corticosteroids.

Secondary complications require first the recognition that an intervening process exists and then that it be identified and treated.

●Dry eyes and night blindness are managed by giving the patient vitamin A, either parenterally or in a liquid preparation for oral ingestion and easy absorption.

●Exudative retinal detachment requires clarification of whether it is secondary to scleritis or from a remote abscess.

●Cataract is managed according to its nature. Early posterior subcapsular opacities have, in the author’s experience, stopped progressing when systemic corticosteroids were stopped. However, the activity of the intestinal disease may require continuation of corticosteroids. In young people, visually disabling cataract is well managed by extracapsular, irrigation-aspiration techniques through a small limbal incision.

●Papillitis from posterior scleritis usually responds to systemic corticosteroids.

●Endophthalmitis caused by bacteria or fungi can be aggressively managed by diagnostic and therapeutic vitrectomy, which provides an organism for culture and removes the mass of infected vitreous. Appropriate antimicrobial therapy depends on identification and sensitivity studies.

Coincidental ocular disease requires only that the ophthalmologist recognize that it is not related to the intestinal disorder. Management is the same as would be given to any patient.

Management of a patient with an ocular complication of Crohn’s disease or ulcerative colitis is difficult and timeconsuming. Efforts must be expended to clarify the status of

the intestinal disease and to communicate with the other physicians involved.

REFERENCES

Baldassano VF, Jr: Ocular manifestations of rheumatic diseases. Curr Opin Ophthalmol 9(6):85–88, 1998.

Bayless TM, Tokyer AZ, Polito JM, II, et al: Crohn’s disease: concordance for site and clinical type in affected family members-potential hereditary influences. Gastroenterology 111:573–579, 1996.

Blase WP, Knox DL, Green WR: Granulomatous conjunctivitis in 2 patients with Crohn’s disease. Br J Ophthalmol 68:901–903, 1984.

Bredvik BK, Trocme SD: Ocular manifestations of immunological and rheumatological inflammatory disorders. Curr Opin Ophthalmol 6(6):92–96, 1995.

Carty E, Rampton DS: Evaluation of new therapies for inflammatory bowel disease. Br J Clin Pharmacol 56(4):351–361, 2003.

Cheung O, Regueiro MD: Inflammatory bowel disease emergencies. Gastroenterol Clin North Am 32(4):1269–1288, 2003.

Hopkins DJ, Horan E, Burton IL, et al: Ocular disorders in a series of 332 patients with Crohn’s disease. Br J Ophthalmol 58:732–737, 1974.

Lindberg E, Janerot G, Huitfeldt B: Smoking in Crohn’s disease: effect on localization and clinical course. Gut 33:779–782, 1992.

Polito JM, II, Childs B, Mellits ED, et al: Crohn’s disease: Influence of age at diagnosis on site and clinical type of disease. Gastroenterology 111:580–586, 1996.

Polito JM II, Rees RC, Childs B, et al: Preliminary evidence for genetic anticipation in Crohn’s disease. Lancet 347:798–800, 1996.

Rudy AJ, Jampol LM: Crohn’s disease and retinal vascular disease. Am J Ophthalmol 110:349–353, 1990.

Salmon JF, Wright JP, Bowen RM, Murray AD: Granulomatous uveitis in Crohn’s disease: A clinicopathologic case report. Arch Ophthalmol 107:718–719, 1989.

66 HYPOVITAMINOSIS 066

(Xerophthalmia, Keratomalacia,

Nutritional Blindness)

Ejaz A. Ansari, BSc(Hons), MBBCh, FRCOphth, MD

Maidstone, England

ETIOLOGY/INCIDENCE

Several different vitamins and minerals are required for eye health, although vitamin A has a pivotal role. The need for adequate vitamin A to prevent xerophthalmia and night blindness, especially in developing countries, is well described. Xerophthalmia impairs the vision of 5–10 million children annually, causing irreversible blindness in 500,000 of these. Children and women in developing countries, and even immigrants who follow their traditional dietary patterns, become deficient because of poor dietary consumption of preformed vitamin A (egg yolk, liver, dairy products) or provitamin A carotenoid-containing foods (green leafy vegetables, carrots, mango). Poor diets are exacerbated by diarrhea, gastroenteritis, and parasitic infections that reduce absorption of vitamin A and by frequent respiratory and other infectious diseases that increase vitamin A excretion or demand.

In developed nations, vitamin A deficiency and xerophthalmia are most commonly a consequence of poor absorption (regional enteritis, cystic fibrosis), liver disease (cirrhosis, hepa-

titis), poor diet (alcoholism, certain vegetarian diets) or selfimposed bizarre diets.

Vitamin A (retinol) is a necessary component of rhodopsin; deficiency results in impaired adaptation to darkness. As retinoic acid, vitamin A is essential for normal differentiation of mucus-secreting epithelia in the eye and many other epithelial-lined organs such as the respiratory and genitourinary tracts. Retinoic acid regulates the expression of more than 300 genes, affecting the immune response and therefore the risk of severe infectious disease.

Vitamin-B deficiency may also cause visual loss. Nutritional amblyopia, manifesting as scotomas, can result from hypovitaminosis B1. Keratitis (hypovitaminosis B2), corneal neovascularisation (hypovitaminosis B6) and optic neuropathy (hypovitaminosis B12) can also occur, and can be improved with adequate vitamin supplementation. Ocular hemorrhage is associated with vitamin C deficiency, or scurvy.

COURSE/PROGNOSIS

Simple, gradual depletion of vitamin A results in the appearance of xerophthalmia of sequentially increasing severity (XN, X1, X2, X3). Acute decompensation leads to the sudden occurrence of corneal ulcers, keratomalacia, or both. The milder forms (XN through X2, XF) respond rapidly within 1 to 7 days to vitamin A therapy, without leaving sequelae. Localized corneal ulcers also heal rapidly, usually within 1 to 2 weeks, leaving a localized scar of varying density. Localized keratomalacia heals more slowly, leaving a dense leucoma adherens. Limbus-to-limbus keratomalacia is gradually replaced by an opaque fibrovascular scar. The anterior chamber is invariably lost, with resulting staphyloma or phthisis. Treatment can still save the other eye, if involvement is less severe, as well as increase the likelihood of survival.

DIAGNOSIS

Vitamin A deficiency results in systemic and ocular manifestations. The systemic consequences are protean and often overlooked: increased severity of infectious disease, increased mortality, growth retardation and anemia. The ocular manifestations are almost pathognomonic and are summarized in the classification by ten Doeschate (see Table 66.1).

Salient characteristics that point to hypovitaminosis are:

●Corneal ulcers (sometimes secondarily infected) but otherwise lacking a ragged, inflamed appearance.

●History of preexisting night blindness in cases of gradually occurring deficiency.

●Presence of underlying causal factors for vitamin A deficiency (e.g. cystic fibrosis).

●Impaired dark adaptation.

●Depressed serum retinol.

Differential diagnosis

●Hereditary causes of night blindness.

●Traumatic or infectious ulcer or both.

●Superficial measles keratitis.

PROPHYLAXIS

The most important preventive measure is a well-balanced diet. In the developing world, prevention is achieved by periodic

Hypovitaminosis • 66 CHAPTER

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67OCULOCEREBRORENAL SYNDROME 270.8

(Lowe Syndrome)

Deborah M. Alcorn, MD

Stanford, California

Oculocerebrorenal syndrome of Lowe (OCRL), or Lowe’s syndrome, is an X-linked recessive multisystem metabolic disorder involving the eyes, nervous system and kidneys. It is characterized by congenital cataracts, glaucoma, motor retardation, intellectual impairment, muscular hypotonia, seizures, renal tubular dysfunction (Fanconi’s syndrome), metabolic acidosis, proteinuria, and aminoaciduria. These patients often exhibit a characteristic facial appearance of frontal bossing, enophthalmos, and full cheeks. Female carriers demonstrate characteristic lenticular opacities, though they have normal renal and neurologic functions.

OCRL has been mapped to Xq25–26. The OCRL 1 gene has been cloned. The gene encodes a phosphatidylinositol-4,5- biphosphate 5-phosphatase in the trans-Golgi complex.

ETIOLOGY/INCIDENCE

●Caused by reduction of phosphatidyliositol-4,5-biphosphate 5-phosphatase and accumulation of phosphatidylinositol- 4,5-biphosphate (PIP2) with a disequilibrium of the phosphoinositides.

●PIP 2 is known to be involved with cellular signallng, protein trafficking and actin polymerization, but the exact mechanism responsible for the disease remains uncertain.

●Rare disease: 1 in 200,000 to 500,000 live births.

●The vast majority of patients are male. A few cases are reported in females, often with X autosome translocation involving the OCRL1 locus.

COURSE/PROGNOSIS

Congenital bilateral cataracts are the hallmark of this disease. Lens abnormalities have been described in 20and 24-week fetuses. Bilateral leukokoria is evident at birth, often with miosis, shallow chamber, and microphthalmos. These cataracterous lenses are small and discoid and histopathology shows an absence of demarcation between nucleus and cortex, indicat-

ing a retarded maturation. The posterior capsule is irregular, with warty excrescenses indicating abnormal function of posterior lens epithelium. If untreated, they may develop nystagmus and dense amblyopia. Best corrected visual acuity is infrequently better than 20/70 despite optimal management. Glaucoma is usually detected within the first year of life and develops in 50% to 70% of patients, usually by age 6. It is usually bilateral and of a primary nature. Corneal keloids may develop in up to 25% of patients, usually after age 5. They extend through the entire thickness of the cornea.

The initial neurologic manifestation of the disease is infantile hypotonia. After 1 year of age, deep tendon reflexes are absent. Up to 50% of patients have seizures, but there is no characteristic seizure type. There is a poorer prognosis for intellectual development with early-onset seizures and inadequately controlled seizures. The diagnosis of OCRL is compatible with normal intelligence with approximately 25% of patients having IQs in the ‘normal’ range (≥70). Their intelligence appears to be stable over their lifetime, excluding decline to intercedent illness. There is a high incidence of behavioral abnormalities, including tantrums and aggressive and self-injurious behavior.

The last of the clinical triad is renal dysfunction. Renal function and histology are normal in utero but may not always be normal at birth. There is subsequent development of proximal renal tubular acidosis, phosphaturia, aminoaciduria, and proteinuria. Acidosis leads to failure to thrive and metabolic collapse, if untreated. By the second to third decade there is gradual loss of creatinine clearance, with progressive renal failure.

Additional manifestations include arthropathy, joint swelling, and tenosynovitis. Half of the patients over 20 years old have diffuse swellings of both small and large joints and nodules of fingers and feet, which may represent excessive growth of fibroblasts. Fractures are common, particularly in the early childhood years.

At birth, these patients are within the normal growth curve, but fall in length, height, and weight especially by their early 20s. Up to 40% have cryptorchidism.

Patients with appropriate therapy may live to be 30 to 40 years old, generally dying from renal failure, respiratory distress, infection, or status epilepticus in the 2nd to 4th decade of life.

DIAGNOSIS

●Clinical.

●Biochemical.

● Enzyme deficiency analysis, >99% sensitivity.

Metabolism4 ProteinSECTIONof Diorders •

Support group

Lowe Syndrome Association 222 Lincoln Street

West Lafayette, IN 47906 (317) 743–3634

REFERENCES

Kruger SJ, Wilson ME, Jr, Hutchinson AK, et al: Cataracts and glaucoma in patients with oculocerebrorenal syndrome. Arch Ophthalmol 121(9):1234–1237, 2003.

Lavin CW, McKeown CA: The oculocerebrorenal syndrome of Lowe. Int Ophthalmol Clin 33:179–191, 1993.

Lin T, Lewis RA, Nussbaum RL: Molecular confirmation of carriers for Lowe Syndrome. Ophthalmol 106(1):119–122, 1999.

Lowe CU, Terrey M, MacLachan EA: Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation: a clinical entity. Am J Dis Child 83:164–184, 1952.

Lowe M: Structure and function of the Lowe syndrome protein OCRL1. Traffic 6:711–719, 2005.

Nussbaum RL, Orrison BM, Janne PA, et al: Physical mapping and genomic structure of the Lowe syndrome gene OCRL 1. Hum Genet 99:145–150, 1997.

Tripathi RC, Cibis GW, Tripathi BJ: Pathogenesis of cataracts in patients with Lowe’s syndrome. Ophthalmol 93:1046–1051, 1986.

Walton DS, Katsavounidou G, Lowe CU: Glaucoma with the oculocerebrorenal syndrome of Lowe J Glaucoma 14(3):181–185, 2005.

68 TYROSINEMIA II 270.2

(Pseudodendritic Keratitis, Recessive

Keratosis Palmoplantaris, Richner–

Hanhart Syndrome)

Stephen P. Christiansen, MD

Minneapolis, Minnesota

ETIOLOGY/INCIDENCE

Tyrosinemia II is a rare autosomal recessive metabolic disorder characterized by herpetiform corneal ulcers and painful keratoses of the hands and feet. It is caused by deficiency of hepatic cytoplasmic tyrosine aminotransferase (cTAT). The gene for this enzyme has been mapped to chromosome 16q 22.1–q22.3. Hepatic mitochondrial TAT levels are normal. Cytoplasmic TAT catalyzes the conversion of tyrosine to p-hydroxyphe- nylpyruvic acid. Deficiency of c-TAT results in elevated plasma tyrosine concentration, tyrosinuria, and tyrosyluria.

COURSE/PROGNOSIS

Tyrosine crystallizes within cells, initiating an inflammatory cascade. Ocular involvement is usually heralded by pain, photophobia, tearing and conjunctival injection. The keratitis has been described as stellate or branching and is initially restricted to the epithelium. Most patients develop bilateral pseudodendritic keratitis early within the first year of life. Onset is variable, however, and ranges from 2 weeks of age to late in the second decade. Some patients never develop ocular findings. As

the disease progresses, corneal ulceration, subepithelial and stromal scarring and corneal neovascularization may occur with resultant visual loss. Cataracts and glaucoma have also been described in untreated patients. Nystagmus and exotropia have been noted in some patients with tyrosinemia II; these may be a consequence of visual loss rather than a primary effect of the disease.

Cutaneous lesions typically occur with or after the eye lesions. They begin as blisters or erosions on the palms and soles, particularly on the tips of the digits and the thenar and hypothenar eminences. The blisters crust and eventually become hyperkeratotic. The lesions are painful but not pruritic and often present in a linear distribution. The severity of cutaneous involvement may wax and wane independently of systemic or topical therapy. Some authors have described symptomatic improvement in ocular and cutaneous symptoms during the summer months. Mental retardation, learning disability, behavioral anomalies, microcephaly, growth retardation, and seizures have been noted in some patients with tyrosinemia II, but are, at best, inconsistent findings.

DIAGNOSIS

Laboratory findings

Serum

●Tyrosinemia is diagnostic. Plasma tyrosine ranges from 16 to 62 mg/dL (normal, 0.6 to 2.1 mg/dL).

Urine

●Tyrosinuria and tyrosyluria.

●Elevated tyrosine metabolites.

●No other amino acids elevated.

Liver biopsy

●Decreased cTAT activity.

Differential diagnosis

●Herpes simplex keratitis: bilateral presentation, minimal staining with fluorescein or rose bengal, negative viral studies, normal corneal sensation and lack of response to topical antiviral therapy allow one to rule out a herpetic etiology.

TREATMENT

Systemic

●Dietary restriction of tyrosine and phenylalanine intake. This diet may be initiated with a prepared formula, such as the Mead Johnson 3200 AB diet. As plasma tyrosine levels decrease, the diet may be liberalized, with the goal of therapy being to maintain plasma tyrosine in the range of 10 mg/dL. Reduction of plasma tyrosine results in fairly rapid resolution of both ocular and cutaneous lesions, both of which will recur if an unrestricted diet is resumed. The effect of dietary control on the occurrence of mental retardation in tyrosinemia II is unknown.

Ocular

●Symptomatic: the early ocular manifestations of tyrosinemia II respond rapidly to dietary therapy. Therefore, initial ocular therapy is usually symptomatic. Topical cortisteroid, antiviral, and antibiotic therapy have all been shown to be ineffective.

II Tyrosinemia • 68 CHAPTER

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