5Disorders of Carbohydrate Metabolism

69 DIABETES MELLITUS 250.0

F. Hampton Roy, MD, FACS

Little Rock, Arkansas

ETIOLOGY/INCIDENCE

Diabetes mellitus is a complex disorder of carbohydrate, lipid, and protein metabolism characterized clinically by hyperglycemia and a relative or total lack of insulin. It is a common disorder that is prevalent worldwide. The development of diabetes is influenced by multiple factors, both genetic and environmental. The disease may develop in the first or second decade of life (type I) or in middle or late life (type II); more than half of diabetic individuals older than 40 years are overweight. A family history of diabetes is positive in 25% of patients. The disease is generally transmitted as a recessive trait without sex linkage.

The increased life span of diabetics due to the use of insulin and other hypoglycemic agents has also resulted in a longer duration of the disease. This is associated with an increased incidence of accelerated atherosclerosis and a triad of retinopathy, nephropathy and neuropathy. The degree of hyperglycemia is also thought to influence the incidence and severity of complications.

Diabetic retinopathy is the most serious ocular manifestation of diabetes mellitus and it causes more blindness among working-age Americans than any other disease. More than 20 million people worldwide are estimated to be blind due to complications from diabetes. Having diabetes increases the risk of blindness by 25%. The etiology is multifactorial and is still not fully understood, but there is evidence to suggest strong relationships between retinopathy and the duration of diabetic disease and high levels of blood glucose.

There is an increasing incidence of diabetes in the United States; an estimated 6% of the population is affected. Of the estimated 16 million diabetics in the United States, about half have retinopathy. Type II diabetes and its complications affect minority populations more than the white population. Native Americans, blacks, and Hispanics have twofold to sixfold higher incidence rates. The rate of clinically detectable retinopathy is less than 25% in patients with a known diabetes of less than 5 years, about 50% with a history of 5 to 15 years, and more than 75% with a history of more than 15 years.

The exact cause of diabetic microvascular disease is not known; possibly, prolonged exposure to hyperglycemia results in glycosylation of tissue proteins with ultimate endothelial

damage. Specific changes that have been noted are the loss of intramural pericytes and basement membrane thickening, which results in obstruction of the capillary lumen and a breakdown of the blood-retina barrier.

Ocular or periocular

●Ciliary body: glycogen deposits in pigment epithelium, thickening of basement membrane.

●Cornea: endothelial pigment deposits, hypesthesia, poor epithelial healing.

●Extraocular muscles: paralysis of third or sixth cranial nerve.

●Iris: ectropion uveae, glycogen deposits in pigment epithelium, pupillary abnormality, rubeosis iridis.

●Lens: cataracts, pigment deposits on epithelium, premature presbyopia.

●Macula: edema, ischemia, exudates, hemorrhage.

●Optic nerve: atrophy, papillopathy.

●Retina: microaneurysms, hard exudates, hemorrhages, cotton-wool spots, venous abnormalities, intraretinal microvascular abnormalities (IRMAs), neovascularization, detachment, arteriolar sclerosis.

●Vitreous: asteroid hyalosis, detachment, hemorrhage.

Diabetic retinopathy

Diabetic retinopathy is the most common and one of the most serious ocular manifestations of diabetes mellitus. Visual loss, often severe, can result through one or more of the following mechanisms: macular edema due to breakdown of the blood– retina barrier, macular ischemia due to occluded perifoveal capillaries, fibrovascular proliferation with associated complications of vitreous hemorrhage, traction detachment of macula, and neovascular glaucoma.

Classification and clinical features of diabetic retinopathy

Two stages are recognized: the early, or nonproliferative (NPDR), stage and the more advanced, or proliferative (PDR), stage. Macular edema can develop during either stage.

NPDR is further described as mild, moderate, severe and very severe. Mild NPDR is characterized by the presence of microaneurysms; retinal edema, or ‘thickening’; and hard exudates. The Early Treatment Diabetic Retinopathy Study (ETDRS) coined the term clinically significant macular edema (CSME) to indicate situations in which edema or hard exudates involved or threatened to involve the center of the fovea. Moderate NPDR additionally presents with cotton-wool spots, IRMAs and venous beading. Severe NPDR is characterized by the presence of four quadrants of significant retinal hemorrhages, two quadrants of significant venous beading, or one quadrant of

Metabolism Carbohydrate5 SECTIONof Disorders •

significant IRMA. This is known as the ETDRS 4, 2, 1 rule. Very severe NPDR is defined as the presence of two or more of these criteria. Severe NPDR can progress to high-risk PDR in 15%, and very severe NPDR can progress to PDR in 45% of patients within 1 year. Venous beading, IRMAs, and extensive capillary nonperfusion on fluorescein angiography are important indicators of significant retinal ischemia.

PDR is further described as early, high risk, or advanced. It is said to occur with the formation of new vessels on the disk (NVD) or elsewhere on the retina (NVE) and with associated proliferation of fibrous tissue. High-risk PDR, as defined by the Diabetic Retinopathy Study (DRS), presents with three or more of the following high-risk characteristics:

●Vitreous or preretinal hemorrhage.

●New vessels.

●New vessels at or within one disk area of the disk.

●Moderate to severe new vessels (NVD equal to or more than one third of the disk area or NVE equal to or more than one half of the disk area).

Advanced PDR is associated with recurrent vitreous hemorrhage, retinal detachment, and neovascular glaucoma. Vision is seriously compromised, and a serious threat of blindness exists.

Fluorescein angiography is of value in the early detection of microangiopathy and in the assessment of macular edema and retinal ischemia. It also aids in photocoagulation.

PROPHYLAXIS

The best way to prevent the major complications of diabetes is probably to keep blood glucose levels as close to normal as possible. The Diabetes Control and Complications Trial (DCCT) has demonstrated that tight blood glucose control through intensive insulin therapy can delay the onset and slow the progression of retinopathy, nephropathy, and neuropathy in type I diabetics. Tightening of blood glucose control is seen to cause a deterioration in retinopathy in some patients with mild or moderate NPDR. This generally stabilizes with time.

TREATMENT

The use of desperate measures such as pituitary ablation has been abandoned because of the associated morbidity and mortality rates. Various pharmacologic agents have been used to treat diabetic retinopathy; the past use of drugs like clofibrate, calcium dobesilate, aspirin, and aldose reductase inhibitors largely reflected the prevalent thinking regarding the possible causes of retinopathy. The ETDRS evaluated the role of aspirin in dosages of 650 mg/day for a possible role in treatment because of its antiplatelet aggregation and fibrinolytic actions. The Sorbinil Retinopathy Trial likewise evaluated the role of an aldose reductase inhibitor (sorbinil) aimed at blocking the effect of the enzyme aldose reductase and thus preventing the formation of toxic levels of sorbitol through the polyol metabolic pathway. None of these drugs have been found to be of value.

Contemporary management of diabetic retinopathy consists of good medical control of diabetes, retinal photocoagulation, and additional vitreous surgery when needed.

Medical

The DCCT has clearly established the value of tight control of blood glucose levels in type I diabetics. Good metabolic control

not only helps to prevent retinopathy but also helps to slow down its progression. Type II diabetes in persons whose diabetes cannot be controlled by diet alone or those who are unwilling or unable to adhere to a restrictive diet can be controlled with oral hypoglycemic agents, insulin, or both. Most type I diabetics require insulin.

Photocoagulation

Retinal photocoagulation is the most successful tool in the treatment of diabetic retinopathy; the landmark studies of DRS and ETDRS have clearly established its value. The DRS proved the value of panretinal photocoagulation (PRP) in high-risk PDR and severe NPDR. The ETDRS, on the other hand, demonstrated the usefulness of macular photocoagulation (grid or focal) in CSME.

Photocoagulation is commonly performed with lasers emitting in the green wave band such as argon or frequency-doubled YAG lasers. Lasers emitting in the red or yellow ranges are useful when there is blood in the vitreous or when treatment is needed very close to the fovea. The treatment technique used for PDR is called ‘panretinal’ or ‘scatter.’ It consists of the application of several hundred 500-μm-diameter burns to the midperipheral and peripheral portions of the retina. Treatment extends posteriorly to two disk diameters from the center of the macula in the temporal quadrants and to one-half disk diameter nasal to the optic disk. In addition, focal treatment using moderate-intensity confluent burns may be applied to new vessels on the surface of the retina. The total number of burns is usually 1200 to 1600, depending on the severity of the retinopathy. Each burn is of a duration of 0.1 to 0.2 second. Power is adjusted to achieve a moderately white burn. The treatment is applied on an outpatient basis with the patient under topical or retrobulbar anesthesia. Focal treatment to new vessels on the optic disk is not necessary.

The regression of neovascularization is usually apparent soon (weeks to months) after treatment, but it is not always complete or permanent. When substantial regression of neovascularization is not obtained or not maintained, one or more additional scatter treatments over previously untreated retina are often followed by satisfactory regression.

The ETDRS recommended treatment of CSME and formulated guidelines that consist of the identification and treatment of all leaking microvascular abnormalities located in an area 500 to 3000 μm from the center of the fovea. The treatment would be focal or in the form of a grid pattern, depending on the nature of the leakage. The burns used to treat the macula are smaller and mild.

The complications of photocoagulation are generally mild and often transient; they include a decrease in light sensitivity, contraction of peripheral visual field, loss of accommodation, and nyctalopia. Intense treatments in a single session have been associated with more serious complications of detachment or hemorrhage of the choroid, macular pucker and subretinal neovascularization.

Surgical

The aims of pars plana vitreous surgery are to remove vitreous hemorrhage, to relieve all traction threatening the macula, and to remove the scaffolding on which fibrovascular proliferation grows. It is required in eyes with severe retinopathy in which there is either nonresolving or recurrent vitreous hemorrhage that prevents vision or the delivery of photocoagulation, increasing vitreoretinal traction posing a threat to the macula from traction detachment, combined traction and rhegmatogenous

detachment, and progressive proliferation uncontrolled with photocoagulation, or, in some cases, with preretinal membrane. The Diabetic Retinopathy Vitrectomy Study emphasized the value of vitrectomy in severe proliferative disease and the usefulness of early vitrectomy (1 to 6 months) in eyes with vitreous hemorrhage in type I diabetics.

COMMENTS

Diabetic retinopathy poses a major threat of blindness to patients with diabetes mellitus. This blindness is preventable in most cases. Early detection and proper diabetic control through diet, exercise, medication, or a combination probably are still the best tools for controlling the disease. Equally important are regular examinations that include ophthalmoscopic examinations through dilated pupils. Should retinopathy be seen, progression should be monitored by an ophthalmologist who can seek specialized care, such as photocoagulation or vitrectomy, at the appropriate time. It must be recognized that pregnancy and concurrent cardiovascular disease are higherrisk situations that require greater care.

Photocoagulation with or without vitrectomy is largely an effective tool to retard the progression of retinopathy; however, it is an invasive procedure that involves some destruction of the retina. Some patients will complain of a decrease in visual acuity or a constriction of the visual fields after the procedure. Current emphasis therefore is on prevention and on the development of new drugs that are safe and have the potential of preventing or arresting the progress of retinopathy. Retinal ischemia is believed to result in the formation of a vascular endothelial growth factor, a molecule suspected to stimulate endothelial cells to multiply and cause neovascularization. Drugs that inhibit the formation of this molecule or block its vasoproliferative effect could play an important role in the management of PDR. Certain protein kinases could block the chemical trigger for angiogenesis. Antihistamines could be of value in preventing breakdown of the blood-retina barrier due to the liberation of bradykinin or serotonin. These agents are being investigated for their therapeutic potential.

REFERENCES

Aiello LP, Avery RL, Arrigg PG, et al: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. New Engl J Med 331:1480–1487, 1994.

American Diabetes Association: Diabetes 1996: vital statistics. Alexandria, American Diabetes Association, 1996:32–33, 51–59.

Carter JS, Monterrosa A, Pugh JA: Non-insulin-dependent diabetes mellitus in minorities in the United States. Ann Intern Med 125:221–232, 1996.

Deb-Joardar N, Germain N, Thuret G, Manoli P, et al: Screening for diabetic retinopathy by ophthalmologists and endocrinologists with pupillary dilation and a nonmydriatic digital camera. Am J Ophthalmol 140(5):814–821, 2005.

Early Treatment Diabetic Retinopathy Study Research Group: Focal photocoagulation treatment of diabetic macular edema. ETDRS Report 19. Arch Ophthalmol 113:1144–1155, 1995.

El-Bradey M, Plummer DJ, Uwe-Bartsch D, Freeman WR: Scanning laser entoptic perimetry for the detection of visual defects associated with diabetic retinopathy. Br J Ophthalmol 90(1):17–19, 2006.

70 GALACTOSEMIAS 271.1

(Galactose-1-Phosphate Uridyl

Transferase Deficiency, Galactokinase

Deficiency, Galactose-6-Phosphate

Epimerase Deficiency)

Deborah M. Alcorn, MD

Stanford, California

ETIOLOGY/INCIDENCE

Galactosemias are autosomal recessive disorders resulting from an error of galactose metabolism caused by a deficiency of any one of three enzymes: transferase, galactokinase, or epimerase. These enzymes catalyze the reactions in the Leloir pathway by which galactose is converted to glucose-1-phosphate. The main dietary source of galactose is mammalian milk, in which it is found in the form of disaccharide lactose. Lactose is then hydrolyzed with the release of the monosaccharides glucose and galactose.

Worldwide estimates of incidence vary from 1 in 18,000 to 1 in 187,000 persons. In the United States, the incidence is approximately 1 in 50,000; it is rare in Asia; and it is more frequent in Europe, with an incidence of 1 in 40,000 persons.

Classic galactosemia, which is the most common and the most severe form, is caused by the impairment of galactose- 1-phosphate-uridyl-transferase (GALT). The gene has been mapped to chromosome 9p13 and cloned. Within days of consuming milk, these infants develop a toxicity syndrome characterized by vomiting, diarrhea, failure to thrive, lethargy, jaundice and hepatomegaly. If left untreated, sepsis (usually E. Coli) and shock are likely. Approximately 30% develop cataracts.

Galactokinase deficiency catalyzes the first step in galactose metabolism (phosphorylation of galactose). The deficiency results from mutation in the GALK1 gene on 17q24. Toxicity in galactokinase deficiency is milder, resulting primarily only in cataracts, usually occurring in the first year of life. The exact prevalence of GALK deficiency is unknown, but felt to be <1/100,000.

The third and rarest type is deficiency of uridine diphosphate (UDP) galactose-4-epimerase, GALE deficiency. UDP galac- tose-4-epimerase catalyzes the third step of galactose metabolism. Two types of epimerase deficiency have been described; one involves only red and white blood cells without metabolic derangement in other tissues and is clinically benign. The other, generalized epimerase deficiency has clinical manifestations similar to those of transferase deficiency and responds to dietary restrictions. GALE deficiency should be considered in patients with liver disease, failure to thrive, increased red blood cell galactose-1-phosphate but with normal GALT enzyme activity.

In infants, the clinical manifestations are toxicity syndromes resulting from exposure to galactose. All three enzyme deficiencies can cause lenticular opacities.

Pathophysiology

Classic galactosemia results in the accumulation of galactose- 1-phosphate and galactose in varying organs with resultant toxicity. In addition, galactitol and galactonate are present

Galactosemias • 70 CHAPTER

Metabolism Carbohydrate5 SECTIONof Disorders •

in significant amounts. Cataract formation is secondary to galactose-1-phosphate accumulation in the lens with its reduction to galactitol with resultant osmotic swelling. This causes loss of plasma membrane redox potential and subsequent cell death.

Proposed theories for the long-term sequelae include in utero damage, chronic self-intoxication by endogenous galactose formation, or depletion of key metabolites.

COURSE/PROGNOSIS

Galactokinase deficiency is the mildest form, manifesting primarily in cataracts. Some patients present with pseudotumor cerebri. These children do not present with the additional systemic manifestations that occur in patients with transferase and epimerase deficiency. Cataracts may develop in heterozygotes.

In transferase and generalized epimerase deficiency, neonatal illness presents soon after the initiation of milk feedings, manifesting with vomiting, failure to thrive, jaundice, hepatomegaly, Escherichia coli sepsis, and cataracts. Most patients present with jaundice in the first few weeks of life distinguishable from physiologic hyperbilirubinemia of the newborn by the degree of elevation in serum total bilirubin or time of onset. Untreated, patients will eventually manifest hepatomegaly, abnormal liver function tests, ascites and renal failure. The mortality rate is high if there is no treatment.

Infant classic galactosemics develop ‘oil droplet’ cataracts in the central lens as well as in the nuclear fibers secondary to galactitol formation in the lens. If left untreated, they may progress to lamellar and, eventually, total cataracts. There may be some reversibility of the lenticular changes if galactose exclusion is initiated early (secondary to resolution of the nuclear edema). Vitreous hemorrhage has been reported, albeit rare.

Despite rapid treatment with strict lactose-galactose restriction, which alleviates the acute toxicity, dietary treatment alone is not sufficient to prevent long-term complications, particularly in transferase-deficient patients. Long-term sequelae consist of speech abnormalities, ovarian failure, ataxia, developmental delay and mental deficiency. Speech and language deficits, associated with a characteristic verbal dyspraxia, are the most recognizable sign of central nervous system dysfunction. Tremors, ataxia, and incoordination become evident during late childhood and adolescence in about one fourth of these patients. Despite dietary restriction, there is poor growth and physical development. There is a high incidence of ovarian failure and pregnancy is rare because of the high incidence of hypergonadotropic hypogonadism with ovarian atrophy. Overall, long term results are disappointing, which may be related to delayed diagnosis and poor dietary compliance.

DIAGNOSIS

Laboratory findings

●Newborn screening: utilizes blood to assay GALT enzyme activity and quantify total red blood cell galactose-1-phos- phate concentration and galactose.

●Any infant with suspicious symptoms, positive newborn screening test, or a positive clinitest reaction and a negative glucostix reaction, deserves measurement of GALT activity.

●Urine for reducing substances: tube test, not dipstick (may be falsely negative if the infant is not feeding well or ingesting non-milk formula).

●Galactosemia: determined by quantitative measurement of erythrocyte galactose-1-phosphate uridyltransferase (GALT) activity and its isoforms by isoelectric focusing of GALT.

●In classic (G/G) galactosemia, affected have GALT enzyme activity <5% of controls.

●In Duarte Variant (D/G) galactosemia, affected have GALT enzyme activity between 5% and 20% of controls.

●Molecular testing:

●Mutation analysis;

●Sequence analysis.

●Prenatal testing available:

●Using both GALT enzyme activity and known family mutations.

●GALE Deficiency: detection of reduced UDP-galactose-4- epimerase activity is diagnostic.

●Slit-lamp examination for any lenticular opacities (faint opacities may be overlooked on indirect ophthalmoscopy).

Additional findings

●Abnormal liver function tests.

●Albuminuria.

●Hyperchloremic metabolic acidosis.

●Hyperaminoaciduria.

Differential diagnosis

●Bilateral cataracts and metabolic disease:

●Hypocalcemia;

●Hypoglycemia;

●Hyperferritinemia;

●Hypoparathyroidism.

●Neonatal hepatotoxicity:

●Alagille syndrome;

●Wilson disease;

●Niemann–Pick disease.

●Sepsis.

TREATMENT

Systemic

●Immediate dietary restriction of all lactose-containing foods and medicines (those that contain lactulose) for transferase and kinase patients:

●Complete absence of galactose prevents formation of complex carbohydrates and galactolipids necessary for metabolic processes;

●Includes not only milk but also some fruits and vegetables (especially watermelon and tomatoes);

●Lifelong dietary commitment, though debated how stringent it should be after early childhood;

●Generally, lactose restriction helps prevent severe liver disease, death from Escherichia coli sepsis, or significant cataracts but no significant effect on central nervous dysfunction or ovarian dysfunction.

●Calcium supplements.

●Speech therapy.

●Developmental evaluation.

●Metabolic geneticist.

●Endocrinologist (evaluation of ovarian status).