ARTIKEL ASLIMEDICINA 2017, Volume 48, Number 2: 133-137

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ABSTRACT

Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology. It can occur at any age but is more frequent in the pediatric population at young age. Because of its infiltration nature, the disease varies widely in clinical manifestation from localized to a multisystem involvement. Owing to the relative rarity of the condition and varies in clinical presentation, it remains a disease in which the diagnosis is often delayed or missed. Jaundice in LCH is a manifestation of liver disfunction. However, a case of cholestasis has been very rare described. We report an 18-months-old boy with LCH involving multiple systems

whose present earlier as cholestasis and recurent fever. The patient was diagnosed following a clinical manifestation of LCH and skin biopsy that revealed Langerhans cells. The patient was in partial remission following chemotherapy and died at fourth months of chemotherapy. In conclusion, any patient presenting to pediatric clinic with jaundice must be rule out the possibility of liver involvement in LCH. Jaundice might be an earlier clinical manifestation of liver disease in LCH and can be a clue for diagnosis. Early diagnosis and proper management would contribute to a better outcome.

Keywords: Langerhans cell histiocytosis, cholestasis, liver disfunction Cite This Article: Lurdes, L., Ketut, A. 2017. Cholestasis as manifestation of langerhans cell histiocytosis in an 18-months-old boy. Medicina 48(2): 133-137. DOI:10.15562/medi.v48i2.42

ABSTRAK

Histiositosis sel Langerhans (HSL) adalah penyakit yang jarang ditemukan, terjadi akibat proliferasi sel Langerhan di berbagai organ tubuh. Penyakit ini lebih sering terjadi pada anak berusia muda dan mempunyai banyak variasi gejala klinis sehingga diagnosis dini menjadi sulit. Manifestasi klinis dapat bersifat lokal maupun melibatkan beberapa sistem. Kolestasis merupakan salah satu manifestasi gangguan fungsi hati karena infiltrasi sel Langerhans namun kejadiannya sangat jarang dilaporkan. Kami melaporkan kasus HSL pada seorang anak lelaki berumur 18 bulan. Penderita berobat pertama kali karena keluhan kuning dan demam lama. Setelah satu

tahun pengobatan, penderita didiagnosis HSL berdasarkan gejala klinis dan hasil biopsi kulit yang konsisten dengan HSL. Penderita menunjukkan perbaikan klinis parsial setelah kemoterapi namun meninggal pada bulan ke empat kemoterapi karena komplikasi HSL. Sebagai simpulan, setiap anak yang berobat dengan keluhan kuning perlu dipikirkan kemungkinan keterlibatan hati pada HSL. Kolestasis dapat merupakan manifestasi klinis awal dan petunjuk diagnosis HSL. Diagnosis dini dan tatalaksana yang sesuai akan memberikan luaran yang lebih baik.

Kata kunci: Histiositosis sel Langerhans, kolestasis, disfungsi hatiCite Pasal Ini: Lurdes, L., Ketut, A. 2017. Cholestasis as manifestation of langerhans cell histiocytosis in an 18-months-old boy. Medicina 48(2): 133-137. DOI:10.15562/medi.v48i2.42

INTRODUCTION

Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal proliferation with unknown etiology. The current nomenclatur used for LCH indicates the disease extent, which may involve a single organ system (unifocal or multifocal) or multiple organs (involving a limmited number or they maybe disseminated).1,2

The annual incidence of LCH has been estimated to be 2 to 10 cases per 1 million children aged 15 years or younger. The male and female ratio is close to one and the median age is 30 months. Any organ or system of the human body can be affected. Liver,

spleen and hematopoetic systems are affected in a small persentage (5 to 10% cases).3,4 Several risk factors have been identified for LCH but strong and consistent associations have not been confirmed.5 The LCH prognosis depends on the extend of disease at presentation. Some prognosis factors have been identified. Age at diagnosis < 2 years portend a worse prognosis but response to therapy at 6 to 12 weeks has been shown to be a mayor important prognostic factor than age. The overall response to therapy is influenced by the duration and intensity of treatment. Involvement of the high-risk organs

Department of Child Health, Medical School of Udayana University/Sanglah Hospital Bali

Email: leaolurdes@yahoo.co.id

Diterima: 12 januari 2017 Disetujui: 14 februari 2017 Diterbitkan: 1 mei 2017

Volume No.: 48

Issue: 2

First page No.: 133

P-ISSN.2540-8313

E-ISSN.2540-8321

Doi: http://dx.doi.org/10.15562/medicina.v48i2.42

Artikel asliCholestasis as manifestation of langerhans cell

histiocytosis in an 18-months-old boy

Leao Lurdes, Ariawati Ketut

134 Medicina; 48(2): 133-137 | doi: 10.15562/Medicina.v48i2.42

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(liver, spleen, and/or bone marrow) is linked to the extent of the disease.6,7

One of the most serious complications of LCH is cholestasis and sclerosing cholangitis. This ussu-aly occurs months after initial presentation, but on occasion may be present at diagnosis, the median is 23 months.8-10

Case illustrationAn 18-months-old boy was admitted to our hospital with a history of jaundice for last 2 months, chronic cough and recurrent fever for an uncertain duration and. He had no history of neonatal cholestasis or neonatal sepsis. Liver function test (LFT) showed total serum bilirubin 1.43 mg/dL with direct fraction of 1.36 mg/dL; serum albumin 2.85 g/dL; Alkaline phosphatase (ALP) 590 mg/dL; Alkaline amino-transferase (ALT) 51.98 U/L; Aspartate amino-transferase (AST) 21.41 U/L; Gamma GT (GGT) 511 U/L. He was treated as a case of pulmonary tuberculosis and intrahepatal cholestasis. He was discharged one month later with antituberculosis

and ursodeoxycholic acid (UDCA) with no marked response. Blood test including liver function test were performed periodically. During outpatient visits, parents complained on and off skin problem. He was reffered to skin doctor and was diagnosed as seborrhoic dermatitis and treated accordingly.

At 22 months old, patient was readmitted to pediatric ward for 3 weeks due to poor oral intake and was assesed as severe malnutrition according to WHO standards. He underwent severe malnutrition protocol. Antituberculosis and UDCA were contin-ued. Two months later, the patient became deeply jaundice (figures 1 and 2) and LFT revealed: total serum bilirubin 16.42 mg/dL with direct fraction of 14.22 mg/dL; Total protein 5 g/dL; serum albumin 2.23 g/dL; ALP 623 mg/dL; ALT 91.1 U/L; AST 101.2 U/L; GGT 826 U/L. Case was suspected as drug induced hepatitis and antituberculosis drugs were suspended for 2 weeks. Patient then was seen regu-larly at outpatient basis. Patient also attended ENT clinic due to chronic and reccurent ear discharge. During that time period, clinical and laboratory findings showed no remarcable improvement which led to descontinuation of antituberculosis drugs.

At 26-months-old, patient was hospitalized due to generalized edema. He was febrile, tachipnic with RR 62x/mnt, deeply jaundice on sclera and skin, abdominal distention, generalized lymphadenop-athy, multiple erythematous papules with desqua-mation on head, chest, back and abdominal area. The anthropometric measurements showed severe malnutrition according to the WHO standards. Laboratory findings as shown in tabel 1 revealed mild anemia with normal total leucocyte and platelet count; peripheral smear revealed microcytic hypo-chromic anemia; Liver chemistries revealed elevated AST, ALT, ALP and GGT; Total serum, direct frac-tion and indirect serum bilirubin were increased; urine was positive for bile; Faal hemeostasis, and electrolites were within normal limits; HbsAg and Anti HCV were non reactive; FNAB showed atypical lymphoid hyperplasia with eosinophylia; abdominal Doppler ultrasonography revealed chronic liver disease with signs of portal hypertention, spleno-megali, thickening of gallblader wall and ascites (figure 3). Histology staining from skin punch biopsy was consistent with langerhans cell histiocy-tosis (figures 4 and 5). Immunohistochemical (IHC) analysis of the skin biopsy showed positive result for S-100 protein. Immunohistochemistry of CD1a was not performed due to unavailability of the test.

He was then reffered to pediatric oncologist and chemotherapy was promptly started based on histiocytosis protocol. Patient was discharged after 1 month on oral chemotherapy of 6-Mercaptopurine 25mg/m2 daily, prednison 20 mg/m2. Clinical presen-tation and laboratory parameter were improved as

Figures 1 and 2 Slight jaundice noticed at first admission and became deeply jaundice

Table 1 Laboratory examinations

Investigations Results

Haemoglobin/TLC 9 g/dL; 8.300/μLPlatelet count 241.000/μLHbsAg/Anti HCV (Elisa) 0.41/0.10 (non reactive)AST/ALT/ GGT/ALP AST 38.9 U/L; ALT 77.6 U/L; GGT 293 U/L;

ALP 518 mg/dLSerum bilirubin/direct fraction/indirect

Total serum bilirubin 11.82 mg/dL with direct fraction of 11 and indirect fraction 0.82 mg/dL

Total serum protein/albumin/globulin fraction

TP 5 g/dL; albumin 2.24 g/dL; globulin 2.76 g/dL

Na/K/Cl and Ca INR; PTT/control; APTT/control

132/3.43/103.8 mmol/L and 8.2 mg/dL1.14; 13.3/11.3; 33.5/56.9 (seconds)

FNAB of colli lymphadenotaphy Atypical lymphoid hyperplasia with eosinophylia

Peripheral smear hypochromic microcytic anemia; normal leucocytes and platelet count; no abnormal cells

Anti HCV, anti hepatitis C virus; AST, aspartate amonitransferase; ALT, alanine aminotransferase; GGT, gamma-glutayl transferase; ALP, alkaline phosphatase; Na, natrium; K, potassium; Ca, calsium; INR, international normalized ratio; PTT, prothrombin time; aPTT, activated partial thromboplastin time; FNAB, fine needle aspiration biopsy; TLC, Total leucocyte count

135Medicina 2017; 48(2): 133-137 | doi: 10.15562/Medicina.v48i2.42

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shown in the following data (figures 6 to 7 and tabel 2). In the fourth month on chemotherapy, patient died due to the complication of CLD.

DISCUSSION

Langerhans cell histiocytosis is a heterogeneous disease, characterized by accumulation of dendritic cells with features similar to epidermal langerhans cells in various organs. The annual incidence of LCH has been estimated to be 2 to 10 cases per 1 million children aged 15 or younger. The median age of presentation has been found to be 30 months. The

male and female children are affected in equal propor-tions.1,2 Any organ or system of the human body can be affected but those more frequently involved are the skeleton ( 80% cases), the skin (33% cases) and the pituitary (25% cases). The other organs involved are the liver, spleen, lungs and hematopoetic systems in a small persentage (5 to 10% cases).3,4 The clinical course may vary from a self-limiting disease to a rapidly progressive one that might lead to death. One of the most serious complications of hepatic LCH is cholestatis and sclerosing cholangitis, considered as a rare case with poor prognostic factor.9,10

The case was an 18-months-old boy who presented with mild jaundice, recurrent fever and cough. Examination done one year later, showed involvement of more then two organs including liver and spleen as high risk organs. The disease was rapidly progress into liver disfunction with signs and symptoms of chronic liver disease (CLD). Patient underwent chemotherapy for 4 months and died due to a massive gastrointestinal bleeding. According to Histiocyte Society, this is a case of high risk multisystem LCH.

Literature analysis in pubmed showed twen-ty-eight cases of pediatric gastrointestinal LCH have been reported. The cause of liver pathology in LCH is due to either direct or indirect effects of the langerhans cells. The indirect effects are reversible and occur due to activation of macrophages in the body leading to hepatomegaly, splenomegaly and hypoalbuminemia; however the langerhans cells are absent on liver biopsy. Whereas in case of direct liver involvement, there are two types of reported liver pathology on biopsy. The first one is an infil-tration of portal tracts without langerhans cells and the second one is characterized by the domi-nation of langerhans cells in the portal tracts and bile ducts.11,12 In our case, we did not perform liver biopsy due to poor condition of the patient.

In a case study of LCH, jaundice has been described rarely. However, LCH can present with earliest features of liver disfunction. On labora-tory investigations, the direct liver involvement is characterized by cholestasis due to the damage of medium to large size of bile ducts with increasing serum of total bilirubin and direct fraction of bili-rubin. Liver function test showed elevation of AST, AST, ALP and GGT. In these patients, the disease is usually chronic and progressive. The portal tract inflamation either due to massive release of cyto-kines or due to proliferating LCs infiltration leads to the development of schlerosing cholangitis and subsequently biliary cirrhosis. Although a portal lymphohistiocytic infiltrate is most characteris-tic, probably cytokine-mediated hepatocellular damage also contribute to substantial functional impairment of liver or even hepatic failure as a

Figures 6 to 7 Clinical features before and after chemotherapy

Table 2 Comparison of figures at admission and following chemotherapy

LFT findingsAt

admission6 months

later Following

chemotherapNormal range

T Bil (mg/dL) 1.43 16.42 9.6 0-1D Bil (mg/dL) 1.36 14.22 9.6 0-0,3ALT (U/l) 51.9 91.9 42.9 0-40AST (U/l) 21.41 101 109 0-40ALP (mg/dL) 590 623 631 0-281GGT (U/l) 511 826 410 8-55TP (g/dL) 6 5 4 5.6-7.5 Albumin (g/dL) 2.85 2.23 3,1 3.5-5.2

T Bil, total bilirubin; D Bil, direct bilirubin; ALT, alanine aminotranferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gama-glutamyl transferase; TP, total protein

Figure 3 Abdominal USG revealed CLD

Figures 4 and 5 Histology stainning consistent with LCH

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presenting feature. Portal tract injury causing occu-rance of sclerosing cholangitis due to langerhans cell histiocytosis is a rare cause of end-stage liver disease, seen mainly in children. Liver involvement is a factor of poor prognosis. Usually, sclerosing cholangitis secondary to LCH responds poorly to treatment.10,11,13

In our case, first clinical presentation were mild cholestasis, recurrent fever with cough. Liver function test (LFT) showed total serum bilirubin 1.43 mg/dL with direct fraction of 1.36 mg/dL; serum albumin 2.85 g/dL; ALP 590 mg/dL; ALT 51.98 U/L; AST 21.41 U/L; GGT 511 U/L. Laboratory find-ings done periodically showed chronic progressive disease (table 2). LFT revealed increased total serum bilirubin and direct fraction; elevated AST, ALT, ALP and GGT; decreased total serum protein and albumin. The finding of abdominal Doppler ultraso-nography was consistent with chronic liver disease (CLD) with signs of portal hypertention, spleno-megali, thickening of gallblader wall and ascites.

Children and adults may develop a red papular rash in the groin, abdomen, back or chest that resem-bles a diffuse candidal rash. Seborrheic involvement of the scalp may be mistaken for a severe case of dandruff in older individuals. Ulcerative lesions behind the ears, involving the scalp, under the breast, genitalia or perianal region are often misdiagnosed as bacterial or fungal infections. Vesicular lesions may be seen and need to be differentiated from herpetic lesion.16 In our case, patient has had chronic skin problem with persistent rash and was attended skin clinic for various time. He has been treated as sebor-rhoic dermatitis and fungal infection. Skin punch biopsy was performed and sent for histopathology examination. The result showed morphologically consistent with langerhans cell histiocytosis.

Since LCH may affect any organ or system of the body, the condition should be considered whenever suggestive clinical manifestations occur in the skin, bone, lung, liver or CNS. The diagnosis is clinico-pathologic. In addition to clinical and radiological features, LCH diagnosis should always be based on histological and immunophenotypic examination of lesional tissue that should be taken from the most easily accesible, yet representative lesion. Based on the International Histiocyte Society recomenda-tions, the presumptive diagnosis established based on conventional histological findings. The presence of this findings, coupled with immunohistochem-ical results showing positive S-100 protein staining supported probable diagnosis. The definitive diag-nosis made if positive CD1a and/or CD207 antigen expression by way of immunohistochemistry.17-19 Diagnosis of LCH is usually made by skin biopsy performed for persistent skin lesions. A liver biopsy is only recommended if there is clinically significant

liver involvement and the result will alter treatment. Liver disfunction is suspected when liver enzymes > 5-fold upper limit of normal; bilirubin > 5-fold upper limit of normal and evidence of hypoalbuminemia. Diagnostic confirmation may be a challenge in some circumstances. In rare cases the risk of biopsy may outweigh the need for a definitive diagnosis, and therefore the risk/benefit ratio should be carefully assesed. In our case, patient was diagnosed as multi-system high-risk LCH based on clinical presentation, laboratory and radiographic findings (table 1), the skin punch biopsy showed morfologically consistent with LCH. Immunohistochemical analysis of the skin biopsy showed positive result for S-100, whereas CD1a and/or CD 207 were not available.

There are general considerations for treatment and criterias for definition of organ involvement in LCH as per histiocytosis society. For liver involvement, the patient may show a combination of symptoms which includes: liver enlargement > 3 cm below the costal margin at the midclavicular line, confirmed by ultrasound or disfunction docu-mented by hyperbilirubinemia > 3 times normal, hypoalbuminemia (< 30 g/dL), GGT increased > 2 times normal, ALT (SGPT)-AST (SGPT) > 3 times normal, ascites, edema, or intrahepatic nodular mass. Spleen involvement if spleen enlargement > 3 cm below margin at the mid clavicular line, confirmed by ultrasound. Skin involvement if any rash documented by histological examination or any lesion (erythematous and crusted macules, papules, or nodules with or without ulceration, or ptechiae, or seborrhoic-like pcture) compatible with the diag-nosis, if LCH is comfirmed by biopsy of another organ. As mentioned before, clinical challenges of multisystem LCH are mortality in young children with involvement of risk organs, and bouts of reacti-vation resulting in morbidity and permanent conse-quences which can occur in all age group. Patients with risk-organ involvement are at risk of death and a poor response to therapy defines a subgroup with a particularly poor prognosis. Several international protocols for MS-LCH treatment have been designed within the framework of the HS.7,8,20 Their main conclusions are: (i) standard treatment is based on steroids and Vinblastin (VBL); (ii) clinical response after first 6 weeks of treatment is a good marker of further disease evolution; (iii) Prolonged treatment for at least 1 year reduces the risk of disease reacti-vations. Front line treatment of MS-LCH are VBL 6 mg/m2 i.v. weekly bolus for 6 weeks, with prednisone 40 mg/m2/day given orally in 3 divided doses for 4 weeks and then tappered over the following 2 weeks. After 6 weeks of treatment, disease status should be reevaluated and treatment continued accordingly. Refractoty disease in patients with liver disfunctions is rare but life threatening situation. Therapeutic

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options include combination chemotherapy should be given. A subset of young children with liver involvement may subsequently develop sclerosing cholangitis that progresses to cirrhosis. Treatment for this children may includes liver transplantation. In our case, we used a histiocytosis protocol by given combination of prednisone and vinblastin as recommended with 6-MP 50 mg/m2/day orally for 6 weeks, Methotrexate 500 mg/m2 intravenously every 2 weeks for 6 weeks and lecovorin 12 mg/m2 every 2 weeks for 6 weeks. After 6 weeks on chemother-apy, clinical status was reevaluated and showed no improvement. Again chemotherapy was continued based on protocol. This situation would prone the patient to a poor prognosis.

Prognosis is closely linked to the extent of disease at presentation when high-risk organs such as liver, spleen and/or bone marrow are involved and to the response to initial treatment. Risk refers to the risk of mortality. Although age younger than 2 years was once thought to portend a worse prognosis, data from the LCH study showed that patients age 2 years or younger without high-risk organ involvement had the same response to therapy as older patients. The high risk designation comes from the high mortal-ity rate (35%) in those who did not respond well to therapy in the first 6 weeks. Response to therapy at 6 to 12 weeks has been shown to be a more important prognostic factor than age. The overall response to therapy is influenced by the duration and intensity of treatment.18-21 In our case, patient was first seen at age younger than 2 years with involvement of high-risk organs. Patient died at fourth month of chemotherapy due to disease complication (CLD).

CONCLUSION

Langerhans cell histiocytosis can occur at any age but is more frequent in the pediatric population. The annual incidence of LCH has been estimated to be 2 to 10 cases per 1 million children aged 15 years or younger. Owing to the relative rarity of the condition, it remains a disease in which the diagnosis is often delayed or missed. Any patient presenting to pedi-atric clinic with jaundice must be rule out the possi-bility of liver involvement in LCH. Jaundice might be an earlier clinical manifestation of liver disease in LCH and can be a clue for diagnosis. Involvement of liver is considered as high risk which might lead to serious complication and death. Therefore the early recognition and promptly treatment would reduce the number of serious complication and even death.

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