Sarcoidosis is a multisystemic disease characterized by the formation of non-necrotizing granulomas.1 Lungs are the most commonly affected organ; however, involvement of other organs such as the liver,2 skin, and heart have been described.3 Pathogenesis of granulomas includes exposure to an environmental trigger in susceptible individuals with various human leukocyte antigen-related genes and immune-related genes.4 The hepatic involvement in sarcoidosis varies between an asymptomatic phenotype in most patients and severe complications such as clinically significant portal hypertension (CSPH) with or without cirrhosis.2,5 Treatment of symptomatic sarcoidosis with organ dysfunction includes corticosteroids and steroid-sparing agents such as methotrexate, azathioprine, and anti-tumor necrosis factor antibodies.6,7 There is a lack of data regarding reversal of CSPH after treatment of sarcoidosis.
A 57-year-old woman originally from Kenya with a medical history of asthma was referred to the National Institutes of Health liver clinic because of granulomatous hepatitis. A year earlier, during an evaluation for abdominal pain and weight loss, a cholestatic pattern of elevated liver enzymes was noted: alkaline phosphatase 217 U/L, gamma glutamyl transferase 147 U/L, alanine aminotransferase 35 U/L, and aspartate aminotransferase 50 U/L with normal total bilirubin and international normalized ratio. The platelet count was 339 K/μL while serum albumin was 3.1 g/dL. No evidence of current or past infection with hepatitis B or C was found. Imaging by magnetic resonance imaging revealed a relatively small liver of 13 cm with heterogenous patchy areas of increased T2 signal. Portal hypertension was evident with a splenomegaly of 22 cm (Figure 1), gastroesophageal varices, splenorenal collaterals, and trace ascites. Percutaneous liver biopsy revealed multiple well-formed, non-necrotizing granulomas, mainly in clusters within and around the portal areas (Figure 2). The granulomas were associated with a mild predominantly lymphocytic infiltrate and fibrosis. A reticulin stain revealed the absence of cirrhosis and vague nodularity suggestive of nodular regenerative hyperplasia (NRH). A CD34 stain was abnormally positive in sinusoidal endothelial cells, consistent with decreased portal vein blood flow. Owing to suspected schistosomiasis, the patient was treated with praziquantel without improvement and thus referred to the National Institutes of Health. On further evaluation, the patient developed progressive dyspnea and cough, and chest imaging revealed parenchymal lung nodules, ground-glass opacities, and numerous mediastinal hilar and paracardiac lymph nodes. A pulmonary evaluation revealed increased angiotensin-converting enzyme levels and mildly obstructive pulmonary function tests. After a bronchoalveolar lavage and endobronchial ultrasound negative for infection, a diagnosis of sarcoidosis was made. Cardiac fluorodeoxyglucose-positron emission tomography revealed no evidence of cardiac sarcoidosis. For further evaluation of CSPH, a transjugular hepatic venous portal pressure measurement was performed and demonstrated a hepatic venous pressure gradient (HVPG) of 13 mm Hg. Treatment was initiated with prednisone 60 mg daily, tapered to a daily dose of 20 mg. Treatment was complicated by significant fluid accumulation necessitating intravenous diuretics and steroid-induced diabetes. Prednisone monotherapy was continued for an additional 6 months with introduction of methotrexate at a dose of 12.5 mg per week allowing for a progressive taper to 5 mg of prednisone daily. During therapy, the patient reported a significant improvement in her respiratory symptoms and abdominal distension. Repeat laboratory test results drawn at this time point revealed an alanine aminotransferase of 30 U/L, aspartate aminotransferase of 35 U/L, alkaline phosphatase 123 U/L, and gamma glutamyl transferase of 58 U/L. The platelet count was 290 K/μL. Repeat magnetic resonance imaging revealed resolution of splenomegaly with a spleen size of 12.5 cm (Figure 3) and resolution of previously observed heterogenous prolonged relaxation characteristics of the liver and ascites.
We report a case of symptomatic hepatic and pulmonary sarcoidosis complicated by CSPH, which responded to immunosuppressive therapy with prednisone and methotrexate. A population-based study from Minnesota including 345 cases of sarcoidosis with over 3 decades of follow-up found only 4 patients with CSPH, all of them cirrhotic.8 Noncirrhotic CSPH due to sarcoidosis is a rare condition. In their landmark report from 1975, Rudzki et al reported 5 cases of hepatic sarcoidosis with CSPH.9 Only 2 of the patients were noncirrhotic on histological evaluation. Currently available data regarding the treatment of extrapulmonary symptomatic sarcoidosis such as hepatic sarcoidosis are derived from retrospective studies and case series. Furthermore, owing to the diverse nature of this multisystemic disease, no consensus exists on the indication for pharmacological management of hepatic involvement. Although previous studies have shown that hepatic sarcoidosis can respond to treatment with corticosteroids and methotrexate,6,7 treatment options for CSPH are limited. A recent consensus report identified the initiation of nonselective β blockers, preferably carvedilol, as advantageous,10 with efficacy in reducing CSPH complications such as variceal bleeding and further hepatic decompensation. However, to the best of our knowledge, reversal of HVPG confirmed CSPH with resolution of ascites, normalization of spleen size, and resolution of liver enzymes has yet to be reported with neither IS therapy nor β blockers. In evaluating this case, one must take into account that HVPG measurements in NRH-associated CSPH are often inaccurate and likely underestimate the true pressure gradient.11 Therefore, a measured HVPG of 13 mm Hg, which is already in the CSPH value range, could possibly suggest the presence of a far higher pressure gradient. In addition, the presence of a significantly enlarged spleen was previously shown to correlate with elevated HVPG in the noncirrhotic portal hypertension setting.12 However, the role of splenic sarcoidosis in the patient's pre-treatment and post-treatment size remains obscure. The reason for CSPH reversal is not entirely clear because a post-treatment liver biopsy and HVPG measurement were not available for review. Thus, it is not clear whether hepatic NRH resolution, regression of hepatic granulomas, changes in vascular flow, or another mechanism provided the pressure relief. Although our case report is unique in the excellent response to immunosuppressive treatment, it demonstrates once again the complexity of sarcoidosis and the significant effect noncaseating granulomas present on the hepatic vasculature. More importantly, it highlights the impression that IS-induced reduction of CSPH despite NRH already present in the hepatic tissue is possible and warrants further investigation.
Author contributions: D. Yardeni wrote the manuscript. J. Hercun, GV Rodriguez, JR Fontana, C. Koh, and T. Heller edited the manuscript and revised it for intellectual content. DE Kleiner provided the pathology images. All authors approved the final version of the manuscript. D. Yardeni is the article guarantor.
Financial disclosure: This work was supported by funding from the Intramural Research Program, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health.
Informed consent was obtained for this case report.
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