Hyperbilirubinemia, Shunt, Primary

Description

Primary shunt hyperbilirubinemia (PSHB) is a rare form of clinical jaundice characterized by increased serum levels of unconjugated bilirubin associated with ineffective erythropoiesis and a hyperplastic bone marrow. Peripheral red blood cell survival is normal (summary by Wang et al., 2006). Although primary shunt hyperbilirubinemia is clinically similar to Gilbert syndrome (143500), affected individuals do not have impaired activity of UDP-glucuronosyltransferase (UGT1A1; 191740). The term 'shunt' refers to a 'shortcut' in bilirubin production, from the bone marrow or from very young red blood cells as opposed to being derived from the hemoglobin of mature circulating erythrocytes (Israels et al., 1959).

Clinical Features

Israels et al. (1959) reported a Mennonite family from southern Canada in which 3 sibs had onset of jaundice in the second decade of life, near the time of puberty. The patients were examined at ages 23, 16, and 26 years, respectively. All had jaundice, marked splenomegaly, spherocytes on peripheral blood smear, and increased reticulocytes; 2 had mild anemia. All had normal circulating red blood cell survival times. Bone marrow biopsies were hypercellular, with normoblastic hyperplasia. The 2 patients with mild anemia underwent splenectomy, which resulted in increased hemoglobin levels and a slight decrease in bilirubin levels, but the bilirubin levels remained above normal. A bilirubin tolerance test showed complete clearance within 3 hours in 1 sib, and 24 to 25% retention at 3 hours in the other 2 sibs. Glucuronide formation with hydroxyacetanilide was normal in 2 patients, indicating that they did not have a defect in UDP-glucuronosyltransferase. An unrelated woman from a neighboring village had a similar phenotype. At age 18 years, she presented with jaundice, anemia, spherocytes, and splenomegaly. She underwent splenectomy but continued to have anemia with increased reticulocytes and a hypercellular marrow. All patients had increased levels of urinary and fecal urobilinogen, also reflecting excess bilirubin accumulation. Liver biopsy of 2 patients showed iron accumulation. Israels et al. (1959) stated that the hyperbilirubinemia in all patients was far in excess of that expected from the hemoglobin level, reticulocyte count, and absence of peripheral erythrocyte destruction, suggesting another source of the bilirubin. Israels et al. (1959) provided a schematic diagram differentiating the condition in these patients from that of hemolytic jaundice and nonhemolytic jaundice due to a conjugation defect. The excess bilirubin in these patients was thought to derive from the bone marrow, directly from heme synthesis or from erythrocyte precursors. The condition should be suspected whenever fecal urobilinogen is markedly increased in the absence of signs of hemolysis. The parents of the sibs were unaffected, although the father reportedly had an episode of jaundice at age 12 years and had a mildly increased reticulocyte count. Israels et al. (1959) suggested that their patients might be related to those described by Kalk (1955) at Kassel, which is not far from Krefeld, formerly a German Mennonite center.

Hamer and Fitzgerald (1973) reported a 17-year-old boy who had mild icterus, splenomegaly, and mild reticulocytosis without anemia, suggesting compensated spherocytosis. Laboratory studies showed erythroid hyperplasia without morphologic abnormalities in the bone marrow and increased unconjugated bilirubin. Extensive cytogenetic and cell proliferation studies of marrow erythroid and myeloid cells showed that about 20% of cells were arrested at metaphase. Some of the chromosomes were highly condensed and degenerate, whereas some were threadlike with separated chromatids. The erythroid series showed a profound disturbance of the cell cycle, with increased numbers of cells in the G2 phase relative to those in S phase, but there was also accumulation of cells in the S phase. The findings suggested that DNA synthesis was interrupted before chromosome replication was completed. In contrast, late normoblasts were unaffected. Hamer and Fitzgerald (1973) hypothesized that intramedullary death of abnormal precursor erythroid cells led to compensatory increased hematopoiesis and a hyperplastic marrow. The destruction of a proportion of these cells results in increased early bilirubin production that characterizes primary shunt hyperbilirubinemia. The authors noted some similarities to congenital dyserythropoiesis (see, e.g., CDAN1, 224120).

Frank et al. (1979) reported a 21-year-old woman who had jaundice and anemia since birth. She had had numerous transfusions. At age 13, she had cholecystotomy due to gallstones and a splenectomy, which did not change the anemia or jaundice. She also had persistent amenorrhea. Physical examination showed hepatomegaly, and biopsy showed severe periportal fibrosis with iron deposition. Bone marrow aspirate showed erythroid hyperplasia and increased iron stores. Laboratory studies showed increased unconjugated bilirubin, fecal urobilinogen, and reticulocytosis. She was diagnosed with primary shunt hyperbilirubinemia with secondary hemochromatosis. Family history revealed a high frequency of jaundice, liver disease, cholecystectomy, and splenomegaly on the paternal side of the family. Her father and sister died with complications of hepatic failure and iron overload. All 3 patients also had severe arthritis, Frank et al. (1979) noted that secondary shunt hyperbilirubinemia is often associated with ineffective erythropoiesis in more common clinical disorders, such as thalassemia (see 613985) and pernicious anemia (261000).

Wang et al. (2006) reported a 4-generation Chinese family in which 9 individuals had primary shunt hyperbilirubinemia. At age 23 years, the proband developed fluctuating jaundice, anemia, and splenomegaly associated with increased serum unconjugated bilirubin levels and reticulocytes. Peripheral blood smear showed irregularly shaped erythrocytes, and bone marrow biopsy showed an erythroid hyperplasia. Family members showed a similar disorder, although 5 also had decreased white blood cell counts. Wang et al. (2006) hypothesized that the disorder results from abnormal development of the erythrocyte and intramedullary ineffective erythropoiesis.

Biochemical Features

Israels et al. (1963) provided evidence for the origin of shunt bilirubin, or bilirubin derived from the early breakdown of heme or its precursors. Their studies indicated that there are 2 components of early bilirubin production distinct from that derived from the normal turnover of peripheral red blood cells. Administration of radiolabeled glycine and delta-aminolevulinic acid, both precursors of heme, to dogs and humans resulted in early appearance of labeled shunt bilirubin at about 1 day and at about 3 to 4 days, respectively. The first peak was not dependent on marrow erythropoietic heme synthesis and may have been formed directly from heme precursors, whereas the second peak was dependent on heme synthesis in the marrow and may be derived from newly-formed erythroblasts.

Inheritance

The transmission pattern of shunt hyperbilirubinemia in the family reported by Wang et al. (2006) was consistent with autosomal dominant inheritance.