Introduction

Sarcoidosis is a systemic inflammatory disease of unknown origin characterized by non-caseating granulomas in multiple organs. Ocular, pulmonary, and cutaneous involvement are the three areas most commonly affected by sarcoidosis in Japan [1]. Hepatic sarcoidosis represents 5–30% of systemic types [2]. The sex- and age-specific incidence rates display a biphasic pattern, with a peak among 20–34-year-old males and a peak among 50–60-year-old females [3].

Hepatic sarcoidosis is usually asymptomatic and most cases do not lead to life-threatening liver disease. However, hepatic involvement can range from mild liver dysfunction to clinically evident disease with cholestasis or, in advanced instances, cirrhosis; with incidental findings of multiple small hypodense hepatic lesions [4].

Hepatic sarcoidosis is diagnosed based on clinical findings consistent with liver disease, histopathologic identification of non-caseating granulomas, and the exclusion of alternative causes of granulomatous disease. Serum angiotensin-converting enzyme (sACE) is one of the most frequently used biomarkers in sarcoidosis diagnosis. However, its sensitivity varies from 60 to 80% and depends substantially on the organ system involved [5]. Most patients with hepatic sarcoidosis have mild biochemical abnormalities. Elevated levels of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) are more common than increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, indicating that the infiltrative nature of sarcoidosis is more characteristic of cholestatic disorders than hepatocellular damage. The severity of any elevation in liver enzyme levels is indicative of the extensiveness of the granulomatous disorder. In liver sarcoidosis, repeated assessment of serum fibrosis markers and liver histology can provide diagnostic insights, aid treatment selection, and determine the best approach to disease management. Despite the brevity of the existing randomized-controlled trials of corticosteroid efficacy, it remains a mainstay of extrapulmonary sarcoidosis treatment. Ursodeoxycholic acid (UDCA) is commonly used as an adjunctive treatment for cholestatic liver disease; although, at the time of writing, no randomized clinical trials of UDCA for hepatic sarcoidosis have been performed. Here, we report the case of a hepatic sarcoidosis patient with histopathological improvements following combined treatment with prednisone and UDCA.

Case report

A 48-year-old Japanese man was referred to the Department of Gastroenterology of Nara Medical University with liver dysfunction that had begun two years earlier. His medical history included ocular and pulmonary sarcoidosis with a biopsy-supported diagnosis and compatible uveitis and epithelioid cell granulomas in the bronchial mucosa, respectively. He was initially treated with corticosteroids, but this was discontinued when blurred vision healed. Our initial medical examination revealed the following: serum alanine aminotransferase (ALT) 39 IU/L, aspartate aminotransferase (AST) 49 IU/L, alkaline phosphatase (ALP) 881 U/L, gamma-glutamyl transferase (GGT) 226 U/L, and total bilirubin 0.8 mg/dL (Table 1). Serum levels of these markers (type IV collagen 7S fragments: 4COL7S; 6.8 ng/ml and hyaluronic acid: HA; 60 ng/mL)W and of angiotensin-converting enzyme (ACE) (31.5 U/L) were elevated. The patient tested negative for hepatitis B surface (HBs) antigen, hepatitis C virus genotype 3 (HCV lll), and antinuclear antibodies (ANA). Ultrasonography found heterogeneous parenchymal echo patterns suggestive of an infiltrative liver disease. It also found homogeneous echogenicity with numerous irregular nodule-like hypo-echogenicities of the liver and spleen (Fig. 1). The first liver biopsy found non-caseating granulomas with fibrous expansion of the portal areas, including occasional portal-to-portal bridging (Fig. 2). After a biopsy sample was obtained from a nodule in the liver, ursodeoxycholic acid (UDCA) treatment at a 600 mg daily dose was initiated. As the patient’s hepatic sarcoidosis did not respond sufficiently to the dose, we increased the dosage to 900 mg/day for 7 months. However, liver enzymes including aminotransferase (ALT) and alkaline phosphatase (ALP) were increased. Therefore, the dose of UDCA was reduced back to 600 mg/day, and prednisolone was initiated at a dose of 30 mg/day and slowly tapered over a 4 month period. The second biopsy findings at a dose of 12.5 mg/day showed significant improvements in the portal inflammation and fibrosis (Fig. 3). The hepatic histological findings from the second liver biopsy showed obvious improvements as a result of the combined administration of corticosteroids and UDCA. The third biopsy was performed 3 years after the second biopsy with the patient on a tapered prednisone dose of 5 mg/day. This biopsy found the portal inflammation and fibrosis to be confined to the portal tracts (Fig. 4). The fourth biopsy following a 5-year course of prednisone at 5 mg/day revealed minimal lobular inflammation and no fibrosis (Fig. 5).

Table 1 Laboratory data
Full size table
Fig. 1
figure 1

Chronological course of the liver (A) and spleen (B) ultrasound of a 48-year-old Japanese man with hepatic sarcoidosis. Yellow arrow indicates hypointense nodule. Irregular nodule-like hypoechoic masses in scattered areas are indicated by yellow arrows

Full size image
Fig. 2
figure 2

First histological examination of a 48-year-old Japanese man with hepatic sarcoidosis. a Azan stain; b hematoxylin–eosin (HE) stain. The first liver biopsy showed advanced fibrosis and non-caseating granulomas. Original magnification × 40 (azan) and × 100 (H&E). c The arrow shows a non-caseating granuloma containing multinucleated Langhans-type giant cells (magnification × 400)

Full size image
Fig. 3
figure 3

Second histological examination of a 48-year-old Japanese man with hepatic sarcoidosis. a Silver impregnation stain; b Azan stain; c hematoxylin and eosin stain (panels a–c: original magnification × 100). Marked improvement was seen in the fibrous enlargement of the portal area and extending fibrous septa

Full size image
Fig. 4
figure 4

Third histological examination of a 48-year-old Japanese man with hepatic sarcoidosis. a Silver impregnation stain; b Azan stain; c hematoxylin and eosin stain (panels a-c: original magnification × 100). Slight fibrous enlargement of the portal area remained

Full size image
Fig. 5
figure 5

Fourth histological examination of a 48-year-old Japanese man with hepatic sarcoidosis. a Silver impregnation stain; b Azan stain; c hematoxylin and eosin stain (panels a–c: original magnification × 40). Mild lobular inflammation was present but without fibrosis

Full size image

Decreased serum levels of ALP, ALT, HA, and ACE were demonstrative of improvements in liver histology (Fig. 6). Levels of the serum macrophage galactose-specific lectin-2-binding protein glycosylation isomer M2BPGi fluctuated slightly but remained essentially unchanged over 2 years. UDCA was continued until corticosteroids were discontinued. After initiating systemic corticosteroids, US revealed that the multiple hypointense nodules in the liver and spleen gradually shrank over time (Fig. 1). Postcorticosteroid therapy initiation, multiple hypointense nodules in the liver and spleen gradually shrank and finally disappeared, as shown in the CT scans (Fig. S2A). Bilateral hilar lymphadenopathy was not detected by chest X-ray film pre- or post-corticosteroid treatment (data not shown). A ground-glass opacity in the right lower lung disappeared shortly after initiating corticosteroid therapy (Fig S2B).

Fig. 6
figure 6

Time course of the case of a 48-year-old Japanese man with hepatic sarcoidosis

Full size image

Discussion

Sarcoidosis is a systemic inflammatory disease that can affect any organ system, including the liver [6]. Hepatic involvement occurs in 11.5% of patients with sarcoidosis [7]. Corticosteroid therapy at an initial dose of 30–60 mg/day is recommended in patients having hepatic sarcoidosis with severe liver dysfunction, by guide to sarcoidosis clinical practice 2020 [8]. Yet, the efficacy and safety of corticosteroid therapy for hepatic sarcoidosis is undetermined. To the best of our knowledge, this is the first case report to show substantial amelioration of pathological liver histology in a sarcoidosis patient treated with combined UDCA and corticosteroids. The four biopsies over the course of the patient’s treatment provide unique insights into the effects of this treatment option. Liver biopsy is the gold standard for assessing chronic hepatitis but has some limitations [9]. Magnetic resonance elastography and transient elastography (FibroScan) were better than noninvasive biomarkers at assessing liver fibrosis in chronic liver diseases, including hepatic sarcoidosis [10, 11]. However, we did not perform either of these assessments in this case.

Advanced cases of hepatic sarcoidosis are often difficult to treat. Recent research has found that a third of patients with hepatic sarcoidosis present with clinically significant portal hypertension, and 14.5% with cirrhosis [12]. Corticosteroid therapy may improve the systemic manifestations of this disease, but the biochemical response to corticosteroids varies in hepatic sarcoidosis. Corticosteroids cannot reverse the progression of liver fibrosis or prevent the development of portal hypertension, so patients are advised to monitor their signs and symptoms for evidence of clinical deterioration [13]. A previous case report found that corticosteroid treatment worsened the progression of symptomatic hepatic sarcoidosis in a patient with a comorbid rupture of the esophageal varices [14]. The pathophysiology of portal hypertension and cirrhosis in sarcoidosis is not fully understood and multiple mechanisms are thought to contribute. Arteriovenous shunting of granulomas in the liver and spleen can increase portal blood flow. This is followed by elevated intrahepatic vascular resistance due to increased vascular tone in the hepatic microcirculation [15]. Intrahepatic resistance can also be attributed to a large confluence of granulomas caused by fibrosis of the parenchyma healing in a haphazard distribution [16]. Thus, contrary to the results in our case, these findings suggest that improvement in liver function parameters after corticosteroid treatment is not accompanied by improvements in liver histology. Glucocorticoids lessen the clinical symptoms and abnormal liver enzymes but may not prevent the progression of hepatic sarcoidosis [7]. In contrast, corticosteroids reduce the number of hepatic granulomas by suppressing the inflammatory response [17], potentially appearing as suppressed hepatic fibrosis. Liver fibrosis typically improves during corticosteroid treatment in patients with autoimmune hepatitis [18]. Moreover, corticosteroid therapy quickly suppresses the progression of liver fibrosis progression due to immune-related acute hepatitis [19]. These findings may account for attenuated progression of liver fibrosis in this present case.

Other treatments for patients with hepatic sarcoidosis include glucocorticoids and immunomodulators. However, it is unclear whether immunosuppressive drugs prevent the progression of the disease or just reduce its manifestation. Hence, corticosteroids can improve hepatic granulomas formation and clinical parameters [20] but may not ameliorate portal hypertension [21, 22]. Prospective randomized-controlled trials to determine the effectiveness and safety of corticosteroids for treating hepatic sarcoidosis are urgently warranted.

At the recommended daily dose of 13–15 mg/kg, UDCA has positive effects on pruritus reduction and liver biochemistry, supporting the empirical use of UDCA in the treatment of hepatic sarcoidosis [23]. The importance of TNF-α in granuloma formation has led to the proposition that cytokines may be a good therapeutic target in sarcoidosis [24]. UDCA inhibits pro-inflammatory cytokines including IL-6 and TNF-α in both humans [25] and experimental animal models [26]. The pharmacological mechanism of action is thought to be the glucocorticoid-like effects of UDCA. The use of UDCA as steroid-sparing agents has been demonstrated in chronic liver diseases [27], but their effectiveness and usefulness in hepatic sarcoidosis remains unresearched. Corticosteroids and UDCA were considered for the patient discussed in this case report, because combination treatment has been shown to improve biochemical responses in the majority of patients with hepatic sarcoidosis [12, 28]. In conclusion, hepatic sarcoidosis is a rare manifestation of extrapulmonary sarcoidosis. However, multiple mechanisms are involved in hepatic sarcoidosis. This case report describes a patient who underwent repeated liver biopsies, which showed that the extent of both the hepatic granuloma and the portal tract fibrosis was markedly reduced by combination corticosteroid and UDCA treatment. However, minimal lobular inflammation was observed during the treatment course and the patient must be followed up carefully and further observations should be made. Nevertheless, we have shown that the combination of ursodeoxycholic and corticosteroids can be an effective treatment for advanced hepatic sarcoidosis.