Alagille syndrome : Resolution of xanthomas

ALAGILLE SYNDROME (ARTERIOHEpatic dysplasia) is an autosomal dominant disorder characterized by chronic cholestasis due to a paucity of intrahepatic bile ducts, characteristic facies, peripheral pulmonary artery stenosis, skeletal abnormalities and ocular posterior embryotoxon (1). Individuals with Alagille syndrome must have two or more of these features (2). The paucity of intrahepatic bile ducts results in a variable degree of chronic cholestasis with elevation of liver enzymes, plasma phospholipids and cholesterol. A case of a 15-year-old male with Alagille syndrome who developed xanthomatosis by age two years with resolution beginning at age 12 years is reported. As little information is available on the resolution of xanthomas and on lipids and lipoprotein profiles in individuals with Alagille syndrome, serum cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and lipoprotein (Lp)-X were assessed in this patient. Lp-X is a low density precursor lipoprotein that is normally excreted in bile but is present in the circulatory system under cholestatic condition (3-6).

When the patient was five years old a repeat liver biopsy showed the characteristic paucity of intrahepatic bile ducts that is seen in Alagille syndrome.Additional features included the characteristic facies of Alagille syndrome with prominent forehead, deep set eyes, hypertelorism, straight nose and small pointed chin.He had a III/VI systolic murmur and a widely split S2 diagnosed as peripheral pulmonary artery stenosis by echocardiogram.Ophthalmic examination showed no posterior embryotoxon and skeletal surveys at age two and 15 years were normal.
He developed problems with xanthomatosis and pruritus around age two years.The xanthomas began on the flexor surface of his forearms and gradually increased in size and spread to the extensor surfaces.By age 12 years he had extensive red-brown xanthomas covering most of the extensor surfaces of his arms, the dorsal aspect of his hands, the anterior and posterior aspects of his thighs, and the posterior aspect of his buttocks and lower back (Figure 1).He had extensive xanthomas on the helices and the posterior aspect of the ears (Figure 2) and small lesions on the buccal mucosa.He had bilateral arcus adiposus and fundoscopic findings of silver wiring, and small tortuous arteries and veins.Exercise tolerance testing and coronary arteries on echocardiogram were normal at age 12 years.Neurological examination and development were normal and he had honours standing in school.At age 15 years he had Tanner II development.Renal function, ultrasound of the liver and alpha-fetoprotein were normal at age 15 years.Chromosome studies were normal with no evidence of a deletion on the short arm of chromosome 20 (20p).Small deletions of 20p can be seen in some individuals with Alagille syndrome.
There was no family history of Alagille syndrome.His parents had normal lipid profiles, and clinical examination showed no evidence of Alagille syndrome.The patient was treated with supplemental vitamins and cholestyramine for pruritus on an intermittent basis before age 10 years.At age 12 years, while undergoing investigations for elevated cholesterol and xanthomas, the patient was placed on a high soluble fibre diet with 30% fat, 140 mg/day cholesterol, 20% protein and 50% carbohydrates.At age 12.5 years he was started on cholestyramine 4 g bid on a regular basis.

RESULTS
Lipid and apolipoprotein profiles are illustrated in Figures 3 to 5. Total plasma cholesterol (Figure 3) was at the extremely high level of 37 mmol/L at age eight years.The patient was lost to follow-up between ages eight and 11 years.At age 12 years the plasma total cholesterol level was 19 mmol/L, well above the upper normal level of 4.9 mmol/L.The lipoproteins that comprise the total plasma cholesterol are illustrated in Figure 4. Low density lipoprotein cholesterol (LDL-C), the majority of the total cholesterol, was well above the upper normal level of 3.18 mmol/L until age 14 years.High density lipoprotein cholesterol (HDL-C) initially was below normal levels but rose steadily to above the normal range (0.88 to 1.53 mmol/L) until age 14 years.Lp-X, a low density precursor lipoprotein, was present in plasma and gradually declined.ApoB (normal 0.67 to 1.17 g/L) declined in parallel with LDL-C and rose when LDL-C increased at 15.3 years (Figure 5).Apoprotein A-I (normal 1.04 to 1.56 g/L) shows a steady rise with a concomitant rise in HDL-C (Figure 5).Total bilirubin, ALT and GGT are illustrated in Figure 6.They were all well above the normal range, with only slight improvement after age 12 years.
The GGT levels were compatible with an obstructive pattern as were bilirubin levels, which fluctuated between 39 and 85 mM/L.
Figure 2 illustrates the presence of xanthomas on the patient's right ear and their resolution from ages 12 to 15 years.The resolution occurred gradually over the course of a number of months starting at 12.2 years of age.Overall, the patient had clinical resolution of xanthomas from age 12 to 13 years with a concomitant decline in total plasma cholesterol, LDL-C and associated apoprotein B. This was associated with a slight increase in HDL-C and the associated apoprotein A-I.

DISCUSSION
Alagille syndrome is an autosomal dominant disorder with features of chronic cholestasis due to paucity of intrahepatic biliary ducts (91%), characteristic facies (95%), peripheral pulmonary stenosis (85%), posterior embryotoxon (prominence of Schwalbe's line 88%) and skeletal abnormalities (87%) including butterfly-like vertebral arch defects or lack of increase in the interpedicular distance of the lumbar spine and short distal phalanges (1,13).A deletion of chromosome 20 (p11.2, p12.3) has been detected in some individuals with Alagille syndrome (14)(15)(16)(17)(18), most of whom show evidence of developmental delay and dysmorphic features suggestive of a contiguous gene syndrome.Much variability has been noted in families with evidence of 'anticipation' which is the increased severity in subsequent generations (14,19).
The patient had the characteristic facies, peripheral pulmonary stenosis and chronic cholestasis due to paucity of intrahepatic biliary ducts.He had an incomplete form with three of the five features of Alagille syndrome, as is seen in 12% of patients (2).His karyotype is normal and his parents had no evidence of Alagille syndrome; therefore he may represent either a new mutation or nonpenetrance in one of his parents.
Intrahepatic cholestasis leads to elevation in liver enzymes and cholesterol.The lipoprotein and lipid profile of our patient was analyzed and showed remarkably high levels of cholesterol, the chief component of which was LDL-C with only low levels of HDL and Lp-X.Cholesterol levels and xanthomas have been shown to improve spontaneously in some cases of Alagille syndrome despite continued cholestasis with elevated bile acid (20)(21)(22)(23).
Previous reports have also demonstrated cholestyramine to be efficacious in the treatment of elevated plasma lipid levels in Alagille syndrome (24,25).Our patient, however, began to show some improvement before initiation of drug or dietary measures.These reports have been of a milder nature with little information on lipoprotein classes.Our patient's total cholesterol LDL-C and Lp-X cholesterol levels and xanthoma improved after age 12 years despite continued cholestasis.He was started on a high soluble fibre diet and cholestyramine which may have influenced the decline in his cholesterol levels.This case illustrates the extraordinarily high levels of cholesterol and massive xanthomatosis that can be seen in individuals with Alagille syndrome.

Figure 1 )
Figure 1) Photograph of buttock covered with xanthomas at age 12 years

Figure 3 )Figure 4 )
Figure 3) Total plasma cholesterol by age in years.Diet therapy began at age 12.2 years and cholestyramine therapy at 12.5 years.The upper normal level for total cholesterol in male children is 4.9 mmol/L