Sarcoidosis-Lymphoma Syndrome presenting by severe Cholestatic Hepatitis

Severe cholestatic hepatitis is an uncommon presentation of either sarcoidosis or Hodgkin lymphoma. Sarcoidosis lymphoma syndrome is a rare disorder with sarcoidosis heralding the onset of lymphoma. Here we report a case of coexisting sarcoidosis-Hodgkin’s lymphoma syndrome presenting with severe cholestatic hepatitis. Case Report Sarcoidosis-Lymphoma Syndrome presenting by severe Cholestatic Hepatitis Omkolsoum M Alhaddad1, Maha M Elsabaawy1*, Omar A Shaarawy1, Nermine A Ehsan2, Doha Maher2, Khaled Gmeel1, Eman A Rewisha1 and Imam A Waked1 1Departments of Hepatology, National Liver Institute, Menoufia University, Shebin El Kom 234511, Egypt 2Departments of Pathology, National Liver Institute, Menoufia University, Shebin El Kom 234511, Egypt Dates: Received: 24 March, 2017; Accepted: 15 May, 2017; Published: 18 May, 2017 *Corresponding author: Maha M Elsabaawy, Departments of Hepatology, National Liver Institute, Menoufia University, Shebin El Kom 234511, Egypt, E-mail: https://www.peertechz.com


Introduction
Sarcoidosis is a multisystem disorder thought to be a result of exaggerated granulomatous reaction to an indeterminate antigen in genetically predisposed persons [1]. Tissue histopathology and comprehensive evaluation are prerequisites of defi nitive diagnosis [2].
Lungs and hilar lymph nodes are the most common sites responsible for the symptomatic disease [3]. Liver affection in sarcoidosis has been variably reported at rates of 11 to 80%, mostly in the form of elevated serum alkaline phosphatase and gamma glutamyl transpeptidase [4]. Clinically evident liver dysfunction occurs at lower rates, even in those with numerous hepatic granulomas [5]. In patients with sarcoidosis, cholestatic hepatitis is rarely seen [6].
Liver dysfunction in lymphoma is common mostly due to drug related hepatotoxicity or hepatic infi ltration [7]. In a rare occasion, lymphoma presents by ductopenia related cholestasis as a paraneoplastic phenomenon [8].
An association between sarcoidosis and lymphoma labeled the sarcoidosis lymphoma syndrome) had been described in case reports since decades [9,10]. In the majority of these reports; sarcoidosis was followed by lymphoma, and exceptionally both coexisting together [11].

Case Presentation
37 years old gentleman presented with a three month history of high grade fever, mostly by night accompanied by profuse sweating with brief days of relieve on antipyretics and antibiotics. One month later, he had started to itch and noticed mild jaundice along with remarkable loss of appetite and weight.
The patient presented to National Liver Institute (NLI) hospital with fever, jaundice, hepatomegaly, and normal By the second week of admission, follow up laboratory data showed persistence of high cholestatic parameters and further rise in serum ferritin (Table 1). CT scanning showed homogenous non-enhancing enlarged right lower deep cervical and paratracheal lymph nodes (size around 1 cm with no calcifi cation or degeneration, bright hepatomegaly with normal pancreatobiliary system and gall bladder. Histopathological examination of a liver biopsy specimen showed a preserved lobular architecture with expanded portal tracts by periportal fi brosis with mononuclear infi ltration, with evident destruction of bile ducts. Parenchyma showed cholestasis with cholestatic rosettes. Portal and parenchymal epithelioid non caseating granulomas were also seen (Figures 1,2). These features strongly suggested the diagnosis of sarcoidosis; which was supported by elevated serum angiotensin converting enzyme (ACE). Prednisolone 60 mg daily was initiated.
By the third week, there was moderate clinical and marked biochemical improvement, including decrease levels of ACE and some sonographic evidence of attenuation of cervical adenopathy.
By the fourth week, fever recurred, right sided deep cervical lymph nodes and the spleen became palpable, and biochemical tests of cholestatic increased. Positron emission tomography (PET)-CT scan showed metabolically active mediastinal, cervical, splenic hilum, left gastric, portahepatis, celiac, portocaval, mesenteric, paraaortic, left internal and external iliac lymph nodes, along with splenic, hepatic, and bone marrow lesions, a picture highly suggestive of lymphoma ( Figure 3).

Discussion
Sarcoidosis typically presents as non-caseating epithelioid granuloma. The fi nding of sarcoid granulomas in the liver is frequent; however, severe hepatic affection is rare [5].
In contrast to sarcoidosis, cholestasis is frequent in lymphoma and could carry poor prognosis [7]. Lymphoma associated cholestasis is mainly due to bile duct compression by a nodal mass or extensive hepatic infi ltration [12]. Stauffer's syndrome, a rare phenomenon, is cholestasis in absence of metastases in patients with renal cell carcinoma and some other cancers [8]. A variant of Stauffer's syndrome; icteric hepatic dysfunction, had been described in Hodgkin's lymphoma mostly due to ductopenia as the underlying pathology [13,14]. Lymphoma related cholestasis in absence of ductopenia is rarely reported and has shown better prognosis [15,16].
The occurrence of lymphoma in the context of sarcoidosis, the so called sarcodiososis lymphoma syndrome, has been observed since decades. An early study reported an 11-fold increase in lymphoma cases among patients with sarcoidosis [9]. When sarcoidosis precedes lymphoma as in the most, or coexisting as in fewer cases, a delay in diagnosing lymphoma can be troublesome [17].
Being a rare manifestation of sarcoidosis, the presence of cholestatic hepatitis in this case raised the possibility of other etiologies, and viral, toxic, and autoimmune disorders were excluded. Presence of non-caseating granulomas in liver tissue and elevated ACE, along with initially clear pulmonary imaging were the reason for early diagnosing the case as isolated hepatic sarcoidosis. Early clinical improvement on steroids with drop of serum levels of ACE and infl ammatory markers supported the diagnosis.
However, in this case; the regression of initial improvement together with the rapidly appearing cervical adenopathy and enlarged spleen questioned the diagnosis of simple sarcoidosis.
In most commentaries of sarcoidosis-lymphoma syndrome (SLS), sarcoidosis was of mild severity, with favorable clinical responses in treated cases [18].
The presence of non-caseating granulomas in lymph nodes draining solid tumors has been mentioned in the literature, labeled sarcoid reaction. However absence of clinical and biological features of sarcoidosis remains the mainstay of differentiation between sarcoid reaction and true sarcoidosis [19]. In this patient, histopathological examination of cervical lymph nodes revealed presence of Hodgkin's lymphoma of nodular sclerosis variety.   Sharquie et al., considered sarcoidosis and lymphoma as a continuum of one disease entity, considering it either sarcoidosis evolving to lymphoma or lymphoma presented by sarcoidosis [20].
Presenting by severe cholestatic hepatitis, this case presented a new spectrum of sarcoidosis lymphoma state. Liver biopsy in this case showed evidence of bile duct destruction but it didn't satisfy the defi nition of vanishing bile duct syndrome; requiring loss of interlobular bile ducts in more than 50% of portal tracts [21].
Conclusively, for the acknowledged sequential linkage between lymphoma and sarcoidosis, the likelihood of yet evolving disease should be considered in every single case of sarcoidosis or lymphoma.

Consent
An informed consent for publication was taken from the patient