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Case report

A severe form of cholestasis lymphoedema syndrome (Aagenaes syndrome) with progressive arthritis

Abdel Ghaffar, Tawhida Y.a,b; Elsayed, Solaf M.a,b

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doi: 10.1097/01.ELX.0000440957.91402.27
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Abstract

Introduction

In 1968, Aagenaes et al.1 first described a syndrome consisting of generalized lymphoedema and cholestasis in families originating from Norway. Later, most of the patients identified with this syndrome were from the same part of the country and molecular analysis has shown that all of them share a common haplotype on chromosome 15q, defining the LCS1 locus 2. To the best of our knowledge, no case has been described from Arab countries.

Case report

Our patient is a 3.5-year-old boy from a poor village in Upper Egypt. He is the second in order of birth of a first-cousin marriage and an outcome of an uncomplicated pregnancy. His birth weight was average. His older brother developed jaundice soon after birth and died at the age of 35 days without any available investigations.

At the age of 10 days, he had an attack of convulsions that was diagnosed as hypocalcaemia. He received calcium and the convulsions did not recur again. At the age of 4 months, the patient started to develop oedema of both hands and feet and at the age of 6 months, jaundice and pruritis were noticed. Several medications were prescribed, but with no improvement. At this point, the patient was referred to our clinic. He had average mental development, whereas his motor developmental milestones were mildly delayed. His weight was 11.5 kg (−3 SD) and height was 78.5 cm (<−4 SD). He had deep jaundice, nonpitting oedema of both feet and legs reaching up to the knee, and of both hands and forearms reaching up to the elbows (Fig. 1). There was also limitation of extension of both knees and elbows and scratch marks all over the body. Abdominal examination showed an enlarged liver (8 cm below costal margin), which was firm in consistency, with a smooth surface and a rounded irregular border. At presentation, the spleen could not be felt. There were no ascites, and his chest and heart examination was clinically free.

Figure 1
Figure 1:
Patient’s legs showing lymphoedema extending to the knee level.

Biochemical investigations at presentation showed total bilirubin of 8.2 mg/dl (N: ≤1), direct bilirubin: 5.2 mg/dl (N: ≤0.3), alanine transaminase level: 161 U/l (N: 42) and aspartate aminotransferase level: 212 U/l (N: 37). Complete blood count showed microcytic hypochromic anaemia with a haemoglobin level of 9.2 g%, normal platelets and white blood cell counts. International normalized ratio was 1, albumin was 3.9 g/dl and gamma-glutamyl transpeptidase (GGT) level was 16.5 (the highest level reached was 24). Cholesterol level was 198 (the highest level was 220). Laboratory investigations indicated no evidence of infection by hepatitis A, B or C.

Radiological

X-ray survey showed bifid T12 and L1 vertebrae and spina bifida of L5 as well as evidence of healed rickets. Abdominal ultrasound showed a normal biliary system and gallbladder.

Liver biopsy showed marked intracellular and canalicular cholestasis. The hepatocytes showed diffuse hydropic and ballooning degeneration. There was minimal number of multinucleated cells. Focal pericellular fibrosis was observed around some of the periportal hepatocytes. The portal areas showed mild to moderate expansion with mononuclear inflammatory cellular infiltrate associated with fibrosis. Short fibrous extensions were observed in some areas and foci of piecemeal necrosis were detected at the limiting plates.

Management

A diagnosis of cholestasis lymphoedema syndrome was made. The patient received ursodeoxycholic acid (20 mg/kg/day), and vitamin E, A, D and K. This was in addition to nutritional therapy and physiotherapy (to reduce lymphoedema). His condition improved gradually in terms of pruritis and jaundice. Alanine transaminase and aspartate aminotransferase levels decreased to 97 and 82 U/l, respectively. Total bilirubin gradually decreased to normal. Five months later, his spleen started to increase gradually in size, reaching four fingers below the costal margin, and his liver started to shrink (Fig. 2). Doppler ultrasound showed a portal vein 10 mm in diameter with collaterals at the hilum of the spleen.

Figure 2
Figure 2:
Patient’s abdomen showing hepatomegaly and splenomegaly.

During his follow-up, it was observed that with each attack of infection, the patient developed cholestasis and grade I hepatic encephalopathy occurred. This responded well to antibiotics and supportive care.

The lymphoedema showed evident improvement with physiotherapy, but recently, he developed enlargement of both knees. Ultrasound of the knees showed bilateral moderate knee joint effusion extending to the supra patellar bursa with small popliteal cysts with clear fluid contents (Fig. 3).

Figure 3
Figure 3:
Patient’s legs showing bilateral knee arthritis.

Discussion

Our patient had typical symptoms of cholestasis lymphoedema syndrome that was described by Oystein Aagenaes in 1968 1. It is a rare hereditary disease consisting of recurrent cholestatic liver disease and generalized lymphoedema from birth or childhood. Most reported patients are from a small region of southwestern Norway 3. Approximately 25 cases have been reported from other countries, including Italy 4, UK 5, USA 6, Poland 7,8, Denmark, Sweden and Greece 9. To the best of our knowledge, no similar cases have been described in this region of the world (Arab countries including Egypt).

Our patient showed several features that are unique to this rare syndrome, one of which is the severity of his liver disease and the progression to liver cirrhosis. In the Aagenaes 1998 review, only four out of 26 patients progressed to cirrhosis from 4 to 8 years of age. It was reported that most patients have a relatively good prognosis compared with patients with other types of hereditary neonatal cholestasis, and more than 50% of patients can expect a normal life span, given proper nutritional and vitamin treatment. Those with remission of liver disease by the age of 2–2.5 years showed a better prognosis 3. This rapid deterioration could be similar to that of the Serbian Romani boy described by Frühwirth et al.9, who needed liver transplantation at the age of 15 weeks.

Another peculiar finding is the inappropriately low GGT and cholesterol levels in relation to the concentration of conjugated bilirubin. This is again similar to the case of the Serbian Romani child described by Frühwirth et al.9, for whom a molecular study was carried out, which indicated no mutation in the 15q9 locus and therefore a second LCS2 was suggested.

The third observation was the presence of progressive arthritis that was not reported previously in any patient with this rare syndrome.

Although molecular analysis has not yet been carried out in our patient, we suggest that our patient, similar to the Serbian Romani patient, could have a different severe form of the disease associated with arthritis and that he has a locus different from LCS1.

Unlike his brother, who died very early, our patient’s cholestasis decreased with time. Although this may be attributed to the proper treatment and care provided, the interfamilial heterogeneity cannot be excluded as these measures do not seem to prevent liver disease from taking a severe course 3.

The recurrence of cholestasis in our patient was because of infection, which supports the previous reports that cholestasis increases with infections, surgery, severe trauma and hormonal effects (puberty, pregnancy and oral contraceptive pills).

The presence of rickets can be attributed to the insufficient vitamin intake before presentation to our centre as children receiving doses of about 500 IU usually develop severe rickets 3.

To conclude, we reported unique characteristics of an Egyptian patient with cholestasis lymphoedema syndrome and the first such patient in an Arabic population. He had a severe form of the disease with progressive cirrhosis and relatively low GGT and cholesterol levels. He also developed progressive arthritis, a feature that has not been described before in this syndrome.

Acknowledgements

The authors thank Dr Hoda Ata, resident of pediatric hepatology, Yassin Abdel Ghaffar Charity Center for Liver disease and research, for her effort in managing the patient.

Conflicts of interests

There are no conflicts of interest.

References

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Keywords:

Aagenaes; arthritis; cholestasis; lymphoedema

© 2014 Egyptian Liver Journal