interferon therapy which is used in hepatitis c therapy can activate one apha hydroxylase inside the macrophage and that can result in hypercalcemia .
we think that internists should be aware of this rare but very serious complication of interferon therapy .
a 48-year - old saudi male patient presented to our emergency room ( er ) with a one - week history of weakness , fatigue and vomiting .
his medical history was significant for the diagnosis of hepatitis c. he denied any history of abdominal pain , hematemesis and melena or bowel problems .
he gave no history of cough , expectoration , hemoptysis and dyspnea or weight loss .
he was started on pegylated interferon alpha therapy 20 weeks prior to his presentation as well as ribavirin treatment for his hepatitis c. on physical examination , he was a well - developed gentleman with no cardiorespiratory distress , but looked confused .
he had no lymphadenopathy and central nervous system examination was intact grossly with negative meningeal signs .
his blood investigations revealed normal complete blood count , renal function tests and blood glucose .
his calcium level was 15.2 mg / dl with albumin level of 3.5 gm / dl .
he was managed by the emergency physician with aggressive normal saline hydration , intravenous pamidronate and hydrocortisone .
laboratory investigation upon patient presentation in the emergency department endocrinology service was consulted and impression of non - parathyroid hormone related hypercalcemia was suggested .
his work - up showed bilateral hilar opacity on chest x - ray , which was confirmed by a computerized scan of the chest showing bilateral hilar lymphadenopathy .
his mediastinal lymph node biopsy showed non - caseating granuloma consistent with sarcoidosis . during his hospital
stay , his mental status improved and his calcium level returned to normal level within 30 days . he was managed with 0.9% normal saline hydration , and furosemide with cessation of his hepatitis c therapy [ table 2 ] .
the ct scan of his chest was repeated two months later and showed complete resolution of the hilar lymphadenopathy without the use of steroid , which confirmed this association .
calcium level during admission this case describes symptomatic hypercalcemia as the initial presenting feature of interferon - induced sarcoidosis during hepatitis c therapy approximately 20 weeks after initiating therapy with pegylated interferon -2b and ribavirin .
the association between interferon therapy for the treatment of chronic hepatitis c and the manifestation of sarcoidosis has been reported in the literature .
multiple case reports have linked the development of sarcoidosis ( de novo reactivation ) to the use of interferon during or after the treatment of chronic hepatitis c. around 70 cases have been reported in the literature so far , the vast majority of which ( approximately 90% ) have been published since 2000 .
a recent review of 50 cases was published by ramos -casals et al . in 2005 . the estimated prevalence of sarcoidosis in the general population ranges from 1 to 40 cases per 100,000 .
thus , the frequency of sarcoidosis seems to be higher in hcv patients receiving antiviral therapy than in the general population .
several case reports outside the setting of hepatitis infection have been reported in patients being treated with interferon for multiple sclerosis , leukemia , lymphoma , kaposi sarcoma and melanoma .
abdi et al , in 1987 published the first case of pulmonary sarcoidosis following the use of interferon for renal cell carcinoma .
patients may be asymptomatic or have vague non - specific symptoms i.e. , fatigue , weakness , malaise , fever and weight loss .
the majority of hcv patients with interferon - induced sarcoidosis present with pulmonary , thoracic , mediastinal lymph node and/or cutaneous involvement .
the mechanism is believed to be related to extra - renal production of calcitriol ( 1,25-dihydroxy - vitated d3 ) by activated macrophages.[1810 ] the resultant high serum calcitriol concentration induces increased intestinal calcium absorption.[1810 ] chronic hypercalcemia may cause a diverse array of signs and symptoms .
the frequency of interferon - related sarcoidosis may be underestimated due to the lack of recognition .
many symptoms of sarcoidosis are non - specific and overlap with the side - effect profile of interferon i.e. , generalized weakness , fatigue , fever , malaise , anorexia , weight loss and arthralgia .
the data observed by ramos - casals et al , showed that nearly 85% of interferon - induced sarcoidosis triggered by an anti - hcv therapy improved or went into remission spontaneously upon cessation of therapy .
severe sarcoidosis involvement ( for example , progressive pulmonary fibrosis , cardiac and neural involvement ) was observed in fewer than 5% .
sarcoidosis was reported to be diagnosed during the first six months after the start of antiviral therapy in 31/47 ( 66% ) ; between 6 and 12 months in 9/47 ( 19% ) and after 12 months in the remaining 7/47 ( 15% ) .
although less frequent , sarcoidosis may not become clinically apparent until after completion of antiviral therapy .
reactivation of pre - existing sarcoidosis after initiation of antiviral therapy for hcv has also been reported in several instances ( 9/66 cases ) .
ramos - casals et al . also reported a potentially higher prevalence of sarcoidosis in the treatment of nave patients with chronic hcv ( 18/68 ) .
he did not find any significant difference when clinical manifestations were compared to the relationship with antiviral therapy .
sarcoidosis is believed to be an immune - mediated process that is generally characterized by an exaggerated t - helper cell ( th-1 ) type 4 immune response with resultant non - caseating granuloma formation in susceptible individuals .
it is believed that interferon provokes a similar exaggerated th-1 immune response both directly and perhaps indirectly by inhibiting th-2 activation .
the th-1 immune response is characterized by the activation of cd4 t - lymphocytes and macrophages ( mononuclear phagocytes ) in affected organs .
these t - lymphocytes also induce the release of th-1 cytokines ( interleukin 2 , interferon - gamma , interleukin-12 ) , a situation which has been repeatedly cited in the pathogenesis of sarcoidosis .
the role of hcv itself as a possible co - factor in the development of the disease has also been postulated because of its own ability to induce a th-1 immune response .
sarcoidosis has been observed in hcv patients who are not on therapy with increased frequency ( 18 cases reported ) suggesting a possible association between sarcoidosis and hepatitis c. this case reiterates previous recommendation that patients need to be carefully monitored for abnormal immunological reactions during ( as early as eight weeks ) and following interferon therapy within six months .
the diagnosis of sarcoidosis may be masked by the insidious development of similar non - specific symptoms shared with the side - effect profile of interferon therapy .
histopathologically , sarcoidosis is characterized by the accumulation of t - lymphocytes and mononuclear phagocytes that form widespread non - caseating epithelioid cell granulomas in the affected organs .
trans - bronchial lung biopsy is recommended in most cases with a diagnostic yield of 4090% exclusion of alternate pathology cincture ( i.e. infectious , neoplastic cause ) is required .
overall , the prognosis for ifn - induced sarcoidosis seems to be good when the medication is discontinued . decision to treat
the data obtained in the ramos  casals review show that nearly 85% ( 38/86 ) of sarcoidosis triggered by anti - hcv therapy improved or remitted spontaneously .
improvement or remission was clear with the discontinuation of antiviral therapy with only 35% of patients requiring systemic corticosteroids . in most large series ,
3050% of unselected patients with sarcoidosis were treated with corticosteroids although the symptoms requiring corticosteroid therapy remain controversial .
antiviral therapy was discontinued in 14% ( 25/42 ) , while sarcoidosis appeared after completion of the therapy in the remaining 11 ( 26% ) cases .
it has been suggested that continuation of interferon therapy or dose adjustment in the presence of a mild exacerbation of sarcoidosis may be safe in a minority of patients with  non - critical organ involvement and close observation .  although data is limited , similar viral response rates to anti - hcv therapy is observed in hcv patients with sarcoidosis compared with unselected hcv patients .
this is the report of a rare case of severe hypercalcemic crisis with bilateral hilar lymphadenopathy in a man who was receiving interferon therapy for hepatitis c. gastroenterologists should be aware of this unusual but clinically important complication of interferon therapy .
 interferon is being increasingly used in the treatment of chronic hepatitis c. several case reports have suggested an association between interferon therapy and sarcoidosis with hypercalcemia . 
 we report a case of severe hypercalcemic crisis with bilateral hilar lymphadenopathy in a male patient who was receiving interferon therapy for hepatitis c. gastroenterologists should be aware of this unusual but clinically important complication of interferon therapy . 
INTRODUCTION
CASE REPORT
DISCUSSION