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Reynolds syndrome

Orpha number ORPHA779
Synonym(s) Primary biliary cirrhosis and systemic scleroderma
Prevalence Unknown
Inheritance Not applicable
Age of onset Adult
ICD-10
  • K74.3
  • L94.0
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Reynolds syndrome (RS) is an autoimmune disorder characterized by the association of primary biliary cirrhosis (PBC) with limited cutaneous systemic sclerosis (lcSSc) (see these terms).

The prevalence of systemic sclerosis (SSc) in PBC patients is 5-15%. Conversely, the prevalence of PBC in SSc patients is about 2%. Females are more affected.

Onset occurs between 30-65 years. RS associates the features of PBC (fatigue, pruritus due to cholestasis, hepatomegaly) with most features of lcSSC (cutaneous calcifications, digital ulcers, facial telangiectasias, calcinosis, Raynaud's phenomenon, esophageal involvement and sclerodactyly). In 50% of cases, symptoms of scleroderma occur prior to those of PBC. About 25-50 % of newly diagnosed RS patients have hyperpigmentation of skin, and jaundice at a later stage. Inflammatory arthropathies are observed in approximately 40% of patients with PBC. In some, RS is associated with other autoimmune diseases such as Sjögren's syndrome, autoimmune hemolytic anemia and (in one case) with thymoma (see these terms). An overlap syndrome between nodular regenerative hyperplasia of the liver (see this term), PBC, and lcSSc may exist.

The pathological mechanism of RS has not yet been established, but it is assumed to be an auto-immune disorder. A heterozygous missense mutation in LBR exon 9 was identified in a Caucasian woman with RS. The mutation was predicted to induce a change in Lamin B receptor tertiary structure. Mutations in LBR may either have a direct pathogenic effect or constitute a predisposing factor in conjunction with other genetic and environmental factors.

Diagnosis of RS relies on the clinical findings for lcSSc and, for PBC, on the biochemical evidence of cholestasis which is based on marked elevation of serum alkaline phosphatase, gamma-glutamyl transpeptidase enzymes and IgM concentrations, a positive test for serum mitochondrial antibody, histologic evidence of non suppurative destructive cholangitis and destruction of interlobular bile ducts. An elevated serum bilirubin is a poor prognostic sign. Specific autoantibodies associated with both facets of the disease (antimitochondrial antibodies for PBC and anticentromere/antitopoisomerase for SSc), and suggestive microscopical abnormalities in the skin and liver have been found in patients affected with RS. Furthermore, a higher prevalence of clonal populations of CD8+ TCRBV3+ T cells has been found in RS.

The association with primary sclerosing cholangitis and SSc is extremely rare. Cholestasis in SSc patients may also reflect liver congestion due to right-sided heart failure in cases with severe pulmonary hypertension. Medications (antibiotics, anabolic steroids, birth control pills, chlorpromazine, cimetidine, estradiol) may cause cholestasis similar to that of PBC.

RS occurs sporadically, but rare familial cases with an unknown inheritance pattern have been observed.

There is no cure for RS and management is mainly supportive. It includes physiotherapeutic assistance and treatment of PBC with ursodeoxycholic acid so as to normalize the cholestatic parameters. Potential hepatotoxic drugs such as bosentan monohydrate or methotrexate can be used to treat some SSc manifestations, if transaminases are < 3 fold the upper limit of normal and remains < 3 fold the upper limit of normal over time.

Nodular regenerative hyperplasia of the liver is a rare complication in those with SSc. Patients usually have a good prognosis, particularly when UDCA treatment is started in the early stages. RS prognosis depends on PBC's severity, but also depends on SSc evolution, as lcSSc has a higher risk of pulmonary arterial hypertension. The regular evaluation of liver function tests is useful for monitoring disease progression. Advanced age, hyperbilirubinemia, low serum albumin and cirrhotic liver biopsy indicate a worse prognosis. Survival of patients with RS seems to be better than that of patients with PBC alone.

Expert reviewer(s)

  • Pr Eric HACHULLA

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