Hyercalcemia induced by interferon therapy in chronic hepatitis C.

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

This very interesting rare case report showed hypercalcemic crises following use of interferon therapy. 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.

CASE REPORT

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 had no history of alcohol drinking or cigarette smoking. He denied any history of unprotected sexual contact or drug abuse. He had a blood transfusion 18 years ago following a road traffic accident. 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. His vital signs were stable. His abdominal examination was soft, lax with no tenderness or organomegaly. His cardiorespiratory examination was normal. 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. He had normal lactate and lipase level. His transaminases were mildly elevated. His calcium level was 15.2 mg/dl with albumin level of 3.5 gm/dl. His parathyroid hormone level (PTH) was appropriately suppressed [Table 1]. He was managed by the emergency physician with aggressive normal saline hydration, intravenous pamidronate and hydrocortisone.

Table 1

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]. A diagnosis of sarcoidosis with severe hypercalcemia induced by interferon therapy was made. This is based on clinical, biochemical, radiological and histopathological criteria. 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.

Table 2

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 α-2b and ribavirin.

DISCUSSION

The association between interferon therapy for the treatment of chronic hepatitis C and the manifestation of sarcoidosis has been reported in the literature.[1] 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.[2]

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.[2] 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.[3]

The clinical manifestation of sarcoidosis is variable. Pulmonary and extrapulmonary involvement is common.[124-7] The development of symptoms is often insidious. 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.[2]

Hypercalcemia occurs in approximately 10–20% cases of sarcoidosis.[16] The mechanism is believed to be related to extra-renal production of calcitriol (1,25-dihydroxy-vitated D3) by activated macrophages.[18-10] The resultant high serum calcitriol concentration induces increased intestinal calcium absorption.[18-10] 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. These symptoms may spontaneously resolve after discontinuation of treatment. Some patients may be completely asymptomatic. Thus, in some individuals, sarcoidosis may potentially go undetected.

The natural history of sarcoidosis is highly variable.[111] Spontaneous remission may occur in about two-thirds of the patients. However, approximately 10–30% may sustain chronic, progressive and permanent sequelae.[1]

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%.[2] 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. This is usually within the first three months of completion of therapy.[2]

Reactivation of pre-existing sarcoidosis after initiation of antiviral therapy for HCV has also been reported in several instances (9/66 cases).[2]

Ramos-Casals et al. also reported a potentially higher prevalence of sarcoidosis in the treatment of naïve patients with chronic HCV (18/68). He did not find any significant difference when clinical manifestations were compared to the relationship with antiviral therapy.[212]

The precise mechanism behind interferon-induced sarcoidosis is not completely understood. 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.[12]

Interferon is an immune modulator that regulates the differentiation of help T-cells. It is believed that interferon provokes a similar exaggerated Th-1 immune response[2] 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.[212]

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.[212] 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. Patients with known sarcoidosis should be monitored closely.

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 40–90%[1] Exclusion of alternate pathology cincture (i.e. infectious, neoplastic cause) is required.[1]

Cessation of interferon (IFN) is thereby sufficient to produce spontaneous remission. Overall, the prognosis for IFN-induced sarcoidosis seems to be good when the medication is discontinued. Decision to treat will depend largely on the sarcoid-related disease. 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. Stabilization of sarcoidosis after initial improvement was found in 6% (3/46).[212]

Improvement or remission was clear with the discontinuation of antiviral therapy with only 35% of patients requiring systemic corticosteroids. In most large series, 30–50% of unselected patients with sarcoidosis were treated with corticosteroids although the symptoms requiring corticosteroid therapy remain controversial.[212] Therapeutic management was specified in 42 cases. 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.