Hepatic Dysfunction in Alström Syndrome

Judy Davis, M.D.,F.A.A.P.,
G-I Clinic, Valley Children’s Hospital, Madera, CA, USA

Alström Syndrome was first described in 1959 by C.H. Alström. It has been mapped to chromosome
2p12-13 and is an autosomal recessive defect. Early manifestations include pigmentary retinal degeneration and blindness, truncal obesity, sensorineural hearing loss, and in some cases infantile cardiomyopathy. Later manifestations can include non-insulin dependent diabetes (type 2), chronic nephropathy, short stature, Acanthosis Nigricans, secondary hypothyroidism, male hypogonadism, alopecia, developmental delay, hypertriglyceridemia, hyperuricemia, kyphoscoliosis, cardiomyopathy and hepatopathy. The hepatopathy can present in the first decade of life. The initial biochemical manifestations of the liver disease are elevated ALT and GGT. During the early phase of the liver disease clinical manifestations are absent. Only later in the disease process do abnormalities of liver function occur with abnormal levels of conjugated bilirubin, prothrombin time, albumin and ammonia as well as laboratory findings of hyperspleenism ( pancytopenia). Late clinical signs include spleenomegaly, enlarged liver followed by a small hard liver, and esophageal varices. Jaundice, pruritis, bleeding diathesis and encephalopathy are very late findings. The disease presents in the liver as a fibrosing and inflammatory process. Lymphocytes infiltrate portal and parenchymal areas with or without piecemeal necrosis and with or without limiting plate destruction. Macrovesicular steatosis can be present or absent. Hepatic inflammation and fibrosis leading to cirrhosis, portal hypertension and liver failure is the final pathway of the hepatopathy in Alström Syndrome. This process does not appear to be an autoimmune process since the usual markers for autoimmune hepatitis are absent (normal ESR, negative anti-nuclear antibodies, anti-liver and kidney microsomal antibodies and anti-double stranded DNA antibodies). In the small number of published case reports and in the authors single case no abnormalities have been found in serum copper, ceruloplasmin, ferritin, alpha-1-antitrypsin phenotype, urine organic acids, plasma amino acids, plasma carnitine, or very long chain fatty acids. Testing for infectious etiologies including EBV , CMV, Hepatitis B, and Hepatitis C have similarly been unrewarding. Upper GI hemorrhage has been the initial symptom leading to death in both reported patients with liver disease and portal hypertension who have died. Aggressive treatment with variceal banding and Inderal is warranted in patients with portal hypertension and varices. Early referral for liver transplant should be done in patients with portal hypertension. Since the hepatopathy of Alstrom Syndrome is clinically silent early in the disease process, yearly testing after 5 years of age with ALT, GGT, alkaline phosphatase and bilirubin should be done to detect those patients who are developing liver disease. When biochemical abnormalities begin, careful follow up for evidence of portal hypertension including physical examination (spleenomegaly), ultrasound with Doppler ( varices, spleenomegaly, cirrhosis, and abnormal portal blood flow), CBC (pancytopenia) and screening esophagogastroduodenoscopy for varices and banding should be done in order to prevent an untimely death due to upper GI hemorrhage from varices. The treatment of the liver dysfunction in Alstrom Syndrome is supportive, as in most other causes of end stage liver disease. At this time there are no preventative measures known that can halt the progression of the liver disease. What also remains unknown in Alström Syndrome is why is there such a wide phenotypic variation in the health and function of the liver