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Keywords:

  • Budd;
  • Chiari syndrome;
  • portal hypertension;
  • primary biliary cirrhosis;
  • sarcoidosis;
  • sclerosing cholangitis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

Sarcoidosis is a systemic granulomatous disease of unknown etiology that involves many organs and has different clinical manifestation. We reviewed the clinical manifestations of sarcoid liver disease. Liver involvement in sarcoidosis can be serious and life-threatening, independent of its lung and other organ involvement.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

Sarcoidosis is a systemic granulomatous disease of unknown etiology and involves many organs. The liver is frequently involved in sarcoidosis, but it seldom gives rise to symptoms. The most common histopathalogical manifestation is non-caseating granulomas1–3 with no evidence of liver dysfunction. Granulomas can be found in approximately 75% of patients with sarcoidosis.1,3 They are small and preferentially located in the portal spaces. Rare clinical hepatic manifestations of sarcoid may include jaundice and chronic cholestasis,4–13 portal hypertension3,8,14–16 or Budd Chiari syndrome.17,18 Intrahepatic cholestasis can resemble primary biliary cirrhosis4–10 or sclerosing cholangitis.8,11–13 Sarcoidosis can also coexist with these two entities.19–24 Extrahepatic biliary tract obstruction in sarcoidosis from enlarged granulomatous lymph nodes has been described.25–27 Cirrhosis and portal hypertension are rare manifestations of sarcoid liver disease, each being found in less than 1% of patients with sarcoidosis.3,8,14–16 We reviewed the clinical manifestations of sarcoid liver disease. The purpose of the present review was to re-emphasize the fact that liver involvement in sarcoidosis can be serious and life-threatening, independent of its lung and other organ involvement.

SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

Clinical characteristics of patients

The first reports of sarcoidosis and portal hypertension were published in 1949 by Mino28 and by Klatskin in 1950.1 Since then, by 2001 an additional 35 patients with sarcoidosis and portal hypertension have been reported in the English medical literature.1–4,14,28–39 Among them, 20 patients had histological evidence of cirrhosis2–4,15,16,31,35,37 and 16 patients had portal hypertension without cirrhosis.2,14,28–34,36,38,39 In one case, the results of the liver biopsy were not known.

Diagnosis of sarcoidosis was based on systemic and pulmonary manifestation, histological evidence of a granulomatous lesion in the liver, lymph node, skin or other tissues, and by the exclusion of known causes of granulomatous disease. The average age of the patients was 35 years. More clinical characteristics of the patients are shown in Table 1.1–4,14–16,28–39

Table 1.  Clinical characteristics of patients with portal hypertension and sarcoidosis
Clinical characteristicPercentage of patients (N = 37)
Male 44
Hepatosplenomegaly100
Ascites 16
Esophageal varices100
Abnormal liver function tests 41

Because there can be reasons other than portal hypertension for ascites and splenomegaly in patients with sarcoidosis, the diagnosis of portal hypertension was made according to direct measurement of pressure in branches of the portal vein in 18 patients,1,4,14,28–33 or according to the finding of esophageal vertices. All the patients had esophageal varices and nearly half had bleeding varices.1,2,14,15,30,32,34–39 Any portal pressure over 200 mm of water (14.6 mmHg) was considered to be elevated. The average portal pressure was 337 mm of water (24.6 mmHg). Fifteen patients had abnormal liver function tests,3,4,15,16,31,33,35,36,38 especially elevation of alkaline phosphatase. Alkaline phosphatase was 2-50 times higher than normal values. The average duration between the diagnosis of sarcoidosis and portal hypertension was 5.7 years. Majority of the patients were treated with splenectomy or portocaval shunts which caused reduction of the portal pressure.2,14,15,28–31,36,38 Glucocorticoids led to little or no improvement in biochemical values and had no influence on portal hypertension or cirrhosis.

Pathophysiology of portal hypertension and cirrhosis in sarcoidosis

Among the described patients, some had elevated portal hypertension without pathological evident of cirrhosis.2,14,28–34,36,38,39 Others had macronodular cirrhosis,37 biliary cirrhosis with predominantly micronodular biliary pattern at autopsy,4 or periportal fibrosis.2,14,15,35,38 The etiology of portal hypertension in sarcoidosis is not completely understood and may involve different mechanisms. Portal hypertension is a function of the portal flow and resistance (portal blood pressure = portal blood flow × resistance). Portal flow can be increased by arterial venous shunts. Maddrey et al.2 suggest that small arterial-venous shunts may be formed in the region of the granulomas in the liver and spleen, resulting in elevated portal blood flow that leads to a compensatory increase in intrahepatic resistance. Resistance can be elevated in the intrahepatic sinusoids by large and confluent sarcoid granulomas that are caused by healing fibrosis of the parenchyma in a haphazard distribution. Development of portal central bridging fibrosis may then give rise to cirrhotic remodeling of the hepatic substance with the potential of portal hypertension occurring.2 The biliary type of cirrhosis is a result of bile duct destruction by granulomas.4,8,10,15,16,40 The resistance can be also elevated presinusoidal, as suggested by Mistilis et al.33 They suggest that the granulomas in the portal areas produce pressure and restrict portal flow, causing a presinusoidal type block. Another theory suggests that cirrhosis and focal fibrosis are caused by ischemia secondary to primary granulomatous phlebitis of portal and hepatic veins,39 which increases the pre- and post sinusoidal resistance. In the lung, vascular involvement in sarcoidosis has been well documented. Granulomatous involvement of pulmonary and bronchial arteries, arterioles, veins, venules and lymphatic vessels has been reported.41 One patient with hepatic granulomatous vasculitis in sarcoidosis has been reported.18 This patient had granulomas in the walls of large- and medium-sized hepatic veins. This leads to the theory that cirrhosis and parenchymal fibrosis in some patients is caused by primary vascular injury. Portal and hepatic vein granulomatous phlebitis was present in the same regions of tissue that were fibrotic.39 Cirrhosis in some patients with sarcoidosis could have been related to coincidental viral or other primary liver disease.2

SARCOIDOSIS AND CHOLESTASIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

Chronic cholestasis, one of the rare expressions of hepatic involvement in sarcoidosis, can be intra or extrahepatic. Chronic intrahepatic sarcoid cholestasis can mimic primary biliary cirrhosis4–10 or sclerosing cholangitis.8,11–13 Extrahepatic sarcoid disease can involve the common hepatic duct or compress the hepatic hilum by adenopathy.25–27

Sarcoid liver disease resembling primary biliary cirrhosis

Primary biliary cirrhosis is an important cause of cholestasis in middle-aged women. The major features of the disease are female predominance, evidence of cholestasis, destruction of the interlobular bile ducts, positive mitochondrial antibody, and the late development of biliary cirrhosis with jaundice, ascites, portal hypertension and bone disease.42 A review of the English medical literature revealed 31 patients with hepatic sarcoidosis and chronic cholestasis with clinical and histological features resembling primary biliary cirrhosis.4–10 Seventeen of the 31 patients were male.4,6,7,8,9 Patients ranged in age from 18 to 75 years. The diagnosis of sarcoidosis was made before, or at the onset, of manifestations of intrahepatic cholestasis, based on evidence of granulomatous disease in two or more organs with no other identifiable cause.4,6–10 Serum angiotensin converting enzyme was raised6,7,9 in four patients and a Kveim Siltzbach test was positive6,7 in three patients. The main clinical manifestations were jaundice,4,6–8 pruritus,4–7 right upper quadrate pain and hepatosplenomegaly.4–10 Alkaline phosphatase levels were elevated: values ranged from 2 to 20 times the upper limit of normal and tests for antibodies to mitochondria were negative in all patients.4–10 Hepatic biopsy specimens showed, besides non-caseating granulomas, a reduction in the number of interlobular bile ducts with evidence of epithelial injury, fibrous tissue linking the portal areas, chronic non-specific inflammatory cell infiltration, and chronic intrahepatic cholestasis with pseudoxanthomatous transformation and increased amounts of copper in hepatocytes.4–10 Glucocorticoid therapy led to improvement in jaundice in one patient.6 Other patients experienced no consistent effect of steroids in preventing progression of the disease.6,7

Although there are rare reports of patients with chronic cholestatic liver disease and clinical features suggestive of both sarcoidosis and primary biliary cirrhosis,19,20 there are some features that serve to differentiate the conditions of chronic intrahepatic cholestasis of sarcoidosis from primary biliary cirrhosis. Characteristically, primary biliary cirrhosis effects women (only 10% of large series are men) of middle age,43 in contrast to a high male : female ratio in cholestasis due to sarcoidosis. Moreover, in sarcoidosis, the natural history of cholestatic disease is much longer than in primary biliary cirrhosis.4–10 Other differentiating features include mitochondrial antibody titer (90% in primary biliary cirrhosis), Kveim Siltzbach skin test (positive result in 80% of patients with sarcoidosis), raised angiotensin converting enzyme (helps to corroborate the diagnosis of sarcoidosis), and normal IgM levels (usually raised in primary biliary cirrhosis).6 In primary biliary cirrhosis, eccentric infiltrates of plasma cells, lymphocytes and eosinophils are seen in relation to damaged bile ducts. Granulomas are common but are usually few in number and often poorly defined. Conversely, in sarcoidosis, bile duct damage is less conspicuous and granuloma are abundant and well formed.6

The pathogenesis of chronic intrahepatic cholestasis in patients with sarcoidosis appears to be progressive destruction of bile ducts by portal and periportal granulomas, with eventual development of biliary cirrhosis. This differs from the apparent pathogenesis of bile duct destruction in primary biliary cirrhosis in which chronic non-suppurative destructive cholangitis appears to be responsible, and granulomas when present are a response to this destruction.44

Sarcoid liver disease resembling sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and progressive fibrosis of the intrahepatic and extrahepatic biliary tree.45 In the English medical literature, there are 16 case reports presenting with severe cholestasis and cholangiographic features of sclerosing cholangitis.8,11–13 Sarcoidosis was diagnosed owing to the presence of non-caseating granulomas in more than two organs,8,12,13 or in one organ with classic respiratory symptoms.11 Eight of the patients were male8,12,13 and patients ranged in age from 18 to 75 years. Clinical manifestations were jaundice, anorexia and abdominal pain.8,11,12 Alkaline phosphatase levels were elevated; values ranged from 2 to 5 times the upper limit of normal and serum titers of neutrophil cytoplasmic antibodies (ANCA) were negative in all patients.11–13 Endoscopic retrograde cholangiography (ERCP) showed segmental dilatation and stricture with beaded intrahepatic ducts.11–13 Liver biopsy revealed focal portal and lobular non-caseating epithelioid cell granulomas surrounded by extensive fibrosis and bile duct proliferation with cholestasis.8,11–13 In one patient, improvement in the liver chemistry and in the appearance of the bile ducts was noted after 3 months of prednisone treatment.11 In another patient, oral steroid treatment caused clinical improvement but the cholestatic biochemical changes persisted and ursodeoxycholic acid was added.12 An endobiliary stent was successfully inserted in another case.13

Although the coexistence of sarcoidosis and primary sclerosing cholangitis was reported in few cases,22–24 there are some features that serve to differentiate the conditions of sarcoidosis resembling sclerosing cholangitis from primary sclerosing cholangitis. The absence of clinical evidence of inflammatory bowel disease, restriction of the narrowing of the bile ducts to a single area in the biliary system, lack of histological features such as concentric periductal fibrosis, absence of ANCA autoantibodies in the serum, normal IgM and improvement with corticosteroid treatment support the diagnosis of sarcoidosis resembling sclerosing cholestasis.11–13 The relatively rapid onset and short duration of the cholestasis, as well as its rapid improvement concomitant with resolution of the strictures with prednisone, suggest an acute intramural or periductal granulomatous process as the dominant pathology, rather than a fibrotic sclerosing process, underlying the ductal lesion.

Sarcoidosis and extrahepatic cholestasis

In the English medical literature, three cases are reported which are rare manifestations of hepatic sarcoidosis with obstruction of the common hepatic duct by sarcoid granuloma.25–27 Two cases are of women and one case is of a man and their age ranges from 29–48 years. Sarcoidosis was diagnosed owing to the presence of non-caseating granulomas in one organ with classic respiratory symptoms, raised angiotensin converting enzyme (ACE) or positive Kveim test.25–27 Clinical manifestations were jaundice, itching, anorexia and abdominal pain.25–27 Hepatic profile showed elevation of alkaline phosphatase, glutamic and hepatic transaminase levels.25–27 Antimitochondrial and antinuclear antibodies were negative. Computer tomography of the abdomen showed intrahepatic biliary dilatation27 and ERCP showed narrowing of the common hepatic duct.25,27 An exploratory laparotomy revealed a nodular mass of confluent lymph nodes surrounding the common hepatic bile duct. Biopsy of the mass showed multiple well-formed granulomas distributed throughout lymphatic tissue and in the wall of the hepatic duct.25,26 In one patient, the symptoms disappeared after insertion of a T tube and steroids.25 The second patient was treated with cholecystostomy26 and the third patient improved with steroids alone; his general condition improved, liver function test and ERCP became normal.

Intra-abdominal lymphadenopathy is common in sarcoidosis and may involve nodes that lie in the hepatic hilum or surround the extrahepatic biliary tract.46 Obstructive complications are rarely observed, probably because the capsular surface of the node remains intact and fixation does not occur. In the presented cases, the obstruction is due to granuloma in the biliary tract causing narrowing of the common hepatic duct.

SARCOIDOSIS AND BUDD CHIARI SYNDROME

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

Hepatic venous thrombosis as a complication of sarcoidosis has only been described in two cases in the English medical literature;17,18 one man and one woman aged 19 and 34 years, respectively. Diagnosis of sarcoidosis was based on evidence of granulomatous disease of two or more organs with no other identifiable cause.17,18 The main clinical manifestations were ascites, jaundice and hepatosplenomegaly.17,18 Alkaline phosphatase was elevated.17,18 Liver biopsy showed, besides granulomas, considerable dilation and congestion of the centrilobular veins and paracentral sinusoids of the hepatic parenchyma, with scattered hepatocytes in these areas undergoing early coagulative necrosis.17 Large and medium sized intrahepatic veins were narrowed by granulomas or were occluded by thrombotic masses.18 Diagnosis of Budd Chiari syndrome was verified by angiography.17,18 One patient was treated with mesocaval anastomosis and steroids17 and the second patient with oral anticoagulation and steroids, showing excellent improvement.18

No other apparent cause of hepatic vein occlusion was demonstrable by history, laboratory studies or anatomic findings by laparotomy. The lumen of these vessels was narrowed by granulomas involving the vessel wall. The development of Budd Chiari syndrome in sarcoidosis was most probably the result of extrinsic compression on hepatic veins by inflammation and edema from sarcoid granulomas, leading to narrowing of venous channels, venous stasis and subsequent thrombosis.17,18

ACUTE SARCOIDOSIS AND LIVER DISEASE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

Acute sarcoidosis develops abruptly over a period of a few weeks and represents 20-40% of all cases.47 These individuals usually have constitutional symptoms such as fever, fatigue, malaise, anorexia or weight loss. Symptoms are usually mild. In approximately 25% of acute cases, the constitutional complaints are extensive.47 Many patients have respiratory symptoms, including cough, dyspnea, vague retrosternal chest discomfort and/or polyarthritis.47 Two syndromes have been identified in the acute group. Lofgren's syndrome, frequent in Scandinavian, Irish and Puerto Rican females, includes the complex of erythema nodosum and radiograph findings of bilateral hilar adenopathy, often accompanied by joint symptoms, including arthritis in the ankles, knees, wrists or elbows. Heerfordt–Waldenstrom syndrome describes individuals with fever, parotid enlargement, anterior uveitis and facial nerve palsy.47

Involvement of the liver in acute sarcoidosis is infrequent. Reviewing the reports of sarcoidosis of the liver in the English medical literature, we found only 10 case reports of patients who presented with jaundice, pruritus and abnormal liver function tests, besides constitutional and pulmonary symptoms in the acute or subacute presentation.5,8,17,27 The rest of the patients presented with clinical features reminiscent of liver disease months or years after the diagnosis of sarcoidosis and the course of the disease was chronic.4,6,7,9,11–13,18–20,26

THERAPY FOR SARCOIDOSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

Sarcoidosis involving organs other than the liver

The therapy of choice for sarcoidosis involving organs other than the liver is glucocorticoids.48,49 Glucocorticoids effectively suppress the activated TH1 lymphocyte processes occurring at the sites of the disease.47 The major problem in treating sarcoidosis is deciding when to treat. Because the disease clears spontaneously in nearly 50% of patients and the permanent organ derangements often do not improve with glucocorticoid treatment, there is controversy among clinicians as to the criteria for treatment.47 When there is evidence of significant impairment of function of a vital organ (heart, lung, brain, kidney or eye), therapy should be instituted immediately. Therapy should also be used for persistent hypercalcemia or hypercalciuria and may be required for diffuse cutaneous lesions.50

Therapies other than corticosteroids as immunosuppressive agents, such as methotrexate and azathioprine, alkylating agents such as cyclophosphamid and chlorambucil, T cell inhibitors such as cyclosporinee and pentoxifylline, and antimalarials such as chloroquine and hydrochloroquine, have been tried for sarcoidosis with varying degrees of effectiveness.50 Although these agents have been helpful in selected patients,50,51 there are few properly controlled studies on which to base decisions regarding efficacy of these therapies versus conventional corticosteroid therapy.50

Sarcoidosis involving the liver

When the only manifestation is non-caseating granulomas, with no evidence of symptoms related to the liver or signs of liver dysfunction, no treatment is needed. In cases of sarcoid liver disease resembling primary biliary cirrhosis, glucocorticoid therapy led to improvement in jaundice in one patient.6 Other patients experienced no consistent effect of steroids in preventing progression of the disease.6,7 In sarcoid liver disease resembling sclerosing cholangitis, improvement in the liver chemistry and in the appearance of the bile ducts was noted after 3 months of prednisone treatment in one patient.11 In another patient, oral steroid treatment caused clinical improvement but the cholestatic biochemical changes persisted and ursodeoxycholic acid was added.12 Endobiliary stent was successfully inserted in another case.13 In one patient with sarcoidosis manifested as extrahepatic cholestasis, symptoms disappeared after steroids and insertion of a T tube.25 The second patient was treated with cholecystostomy26 and the third patient improved with steroids alone, his general condition improved, liver function test and ERCP became normal.

Treatment of sarcoidosis complicated with Budd Chiarri was mesocaval anastomosis and steroids in one patient,17 and oral anticoagulation and steroids with excellent improvement in the second patient.18

Most of the patients with portal hypertension were treated with splenectomy or portocaval shunts which caused reduction of the portal pressure.2,14,15,28–31,36,38 Glucocorticoids led to little or no improvement in biochemical values and had no influence on portal hypertension or cirrhosis.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES

The clinical spectrum of hepatic involvement in sarcoidosis extends from asymptomatic ‘granulomatous hepatitis’ to overt hepatic disease with portal hypertension, intrahepatic, extra hepatic cholestasis, or both. Extrahepatic biliary tract obstruction must be carefully excluded before jaundice in sarcoidosis can be attributed to intrahepatic disease, regardless of liver biopsy findings. Sarcoidosis should be included among the conditions that can produce a syndrome that mimics that of primary biliary cirrhosis, sclerosing cholangitis and Budd Chiari syndrome. A trial of corticosteroid therapy may be of benefit in patients with bile ductal involvement by sarcoidosis.

Although portal hypertension and cirrhosis are not common complications of sarcoidosis, it is very important to be aware of these complications because they can be life-threatening. Ascites and splenomegaly do not necessary indicate portal hypertension and can be due to other causes in sarcoidosis. Approximately half of the patients with sarcoidosis will have portal hypertension without evidence of cirrhosis, so liver biopsy without histological evidence of cirrhosis would not be able to rule out portal hypertension. Varices veins are one of the best indicators of portal hypertension. We recommend that every patient with diagnosis of sarcoidosis should undergo gastroscopia in order to look for varices veins. The only treatments to date that reduce the number of varices bleeding events are splenectomy and portocaval shunt. Splenectomy with or without portacaval shunts should be considered for every patient with sarcoidosis and portal hypertension to reduce the risk of bleeding and prolong their survival.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SARCOIDOSIS, PORTAL HYPERTENSION AND CIRRHOSIS
  5. SARCOIDOSIS AND CHOLESTASIS
  6. SARCOIDOSIS AND BUDD CHIARI SYNDROME
  7. ACUTE SARCOIDOSIS AND LIVER DISEASE
  8. THERAPY FOR SARCOIDOSIS
  9. CONCLUSIONS
  10. REFERENCES
  • 1
    Klatskin G, Yesner R. Hepatic manifestations of sarcoidosis and other granulomatous disease. Yale J. Biol. Med. 1950; 23: 20748.
  • 2
    Maddrey WC, Johns CJ, Boitnott J et al. Sarcoidosis and chronic hepatic disease: a clinical and pathologic study of 20 patients. Medicine 1970; 49: 37595.
  • 3
    Branson JH, Park JH. Sarcoidosis hepatic involvement. Ann. Intern. Med. 1954; 40: 11145.
  • 4
    Rudzki C, Ishar KJ, Zimmerman HJ. Chronic intrahepatic cholestasis of sarcoidosis. Am. J. Med. 1975; 59: 37387.
  • 5
    Thomas E, Micci D. Chronic intrahepatic cholestasis with granulomas and biliary cirrhosis. JAMA 1977; 238: 3378.
  • 6
    Bass NM, Burroughs AK, Scheuer PJ, James DG, Sherlock S. Chronic intrahepatic cholestasis due to sarcoidosis. Gut 1982; 23: 41721.
  • 7
    Pereira Lima J, Schaffner F. Chronic cholestasis in hepatic sarcoidosis with clinical features resembling primary biliary cirrhosis. Am. J. Med. 1987; 83: 1448.
  • 8
    Davaney K, Goodman ZD, Epstein MS, Zimmerman HJ, Ishak KG. Hepatic sarcoidosis clinicopathologic feature in 100 patients. Am. J. Surg. Pathol. 1993; 17: 127280.
  • 9
    Nakanuma Y, Kouda W, Harada K, Hiramatsu K. Hepatic sarcoidosis with vanishing bile duct syndrome, cirrhosis and portal phlebosclerosis. J. Clin. Gastroenterol. 2001; 32: 1814.
  • 10
    Hughes GS, Kataria YP, O'Brien TF. Sarcoidosis presenting as biliary cirrhosis treatment with chlorambucil. South Med. J. 1983; 76: 14402.
  • 11
    Alam I, Levenson SD, Ferreli LD, Bass NM. Diffuse intrahepatic biliary strictures in sarcoidosis resembling sclerosing cholangitis. Dig. Dis. Sci. 1997; 42: 1295301.
  • 12
    Manuel RG, Emilio SG, Angeles OM et al. Sarcoidosis sclerosing cholangitis and chronic atrophic autoimmune gastritis: a case of infiltrative sclerosing cholangitis. J. Clin. Gastroenterol. 1998; 27: 1625.
  • 13
    Debashis D, Alexander S, Thomas W. Hepatic sarcoidosis and renal carcinoma. J. Clin. Gatroenterol. 1999; 28: 613.
  • 14
    Porter GH. Hepatic sarcoidosis. A cause of portal hypertension and liver failure: review. Arch. Intern. Med. 1961; 108: 20516.
  • 15
    Tekeste H, Latour F, Levitt RE. Portal hypertension complicating sarcoid liver disease: Case report and review of the literature. Am. J. Gastroenterol. 1984; 79: 38996.
  • 16
    Valla D, Presseguiro Miranda H, Degott C, Lebrec D, Rueff B, Benhamou JP. Hepatic sarcoidosis with portal hypertension. A report of 7 cases with a review of the literature. Q. J. Med. 1987; 63: 53144.
  • 17
    Natalino MR, Goyette RE, Owensby LC, Rubin RN. The Budd Chiari syndrome in sarcoidosis. JAMA 1978; 239: 26578.
  • 18
    Russi EW, Bansky G, Pfaltz M, Spinas G, Hammer B, Senning A. Budd Chiari syndrome in sarcoidosis. Am. J. Gastroenterol. 1986; 81: 715.
  • 19
    Hughes P, McGavin CR. Sarcoidosis and primary biliary cirrhosis with co existing myositis. Thorax 1997; 52: 2012.
  • 20
    Keeffe EB. Sarcoidosis and primary biliary cirrhosis. Am. J. Med. 1987; 83: 97780.
  • 21
    Stanley NM, Fox RA, Whimster WF, Sherlock S, Jamen DG. Primary biliary cirrhosis or sarcoidosis or both? N. Engl. J. Med. 1972; 287: 12824.
  • 22
    Ilan Y, Rappaport I, Feigin R, Ben Chetriti E. Primary sclerosing cholangitis in sarcoidosis. J. Clin. Gastroenterol. 1993; 16: 3268.
  • 23
    Steenbergen WV, Fevery J, Vandenbrande P. Ulcerative colitis, primary sclerosing cholangitis, bile duct carcinoma and generalized sarcoidosis. J. Clin. Gastroenterol. 1987; 9: 5749.
  • 24
    Shep GN, Scully LJ. Primary sclerosing cholangitis and sarcoidosis: an unusual combination. Can. J. Gastroenterol. 1990; 4: 48994.
  • 25
    Bloom R, Sybert A, Mascatello VJ. Granulomatous biliary tract obstruction due to sarcoidosis. Am. Rev. Res. Dis. 1978; 117: 7837.
  • 26
    Baughman RP. Sarcoidosis usual and unusual manifestations. Chest 1988; 94: 16570.
  • 27
    Rezeig MA, Fashir BM. Biliary tract obstruction due to sarcoidosis: a case report. Am. J. Gastroenterol. 1996; 92: 5278.
  • 28
    Mino RA, Murphy AI, Livingstone RG. Sarcoidosis producing hypertension. Treatment by splenectomy and splenorenal shunt. Ann. Surg. 1949; 130: 9517.
  • 29
    Dunlap RW, Hallenbeck GA, Hanlon DG. Portal hypertension associated with sarcoidosis and with hemochromatosis: report of 2 cases with splenectomy and splenorenal anastomosis. Proc. Mayo Clin. 1952; 27: 26672.
  • 30
    Fraimow W, Myerson RM. Portal hypertension and bleeding esophagial varices secondary to sarcoidosis of the liver. Am. J. Med. 1957; 23: 9958.
  • 31
    Cheitlin MD, Sullivan BH, Myers JE et al. Portal hypertension in hepatic sarcoidosis. Gastroenterology 1960; 38: 609.
  • 32
    Handler S, Blank N. Sarcoidosis as a cause of portal hypertension and esophageal varices. Minn. Med. 1961; 44: 36381.
  • 33
    Mistils SP, Green JR, Schiff L. Hepatic sarcoidosis with portal hypertension. Am. J. Med. 1964; 36: 4705.
  • 34
    Nelson RS, Sears ME. Massive sarcoidosis of the liver. Report of 2 cases. Am. J. Dig. Dis. 1968; 13: 95106.
  • 35
    Vilinskas J, Joyeuse R, Serlin O. Hepatic sarcoidosis with portal hypertension. Am. J. Surg. 1970; 120: 3936.
  • 36
    Rosenberg JC. Portal hypertension complicating hepatic sarcoidosis. Surgery 1971; 69: 2949.
  • 37
    Case records of the Massachusetts General Hospital. Case 1–1979. N. Engl. J. Med. 1979; 300: 2837.
  • 38
    Berger I, Katz M. Portal hypertension due to hepatic sarcoidosis. Am. J. Gastroenterol. 1973; 59: 14751.
  • 39
    Moreno-Merlo F, Wanless IR, Shimamatsu K, Sherman M, Greig P, Chiasson D. The role of granulomatous phlebitis and thrombosis in the pathogenesis of cirrhosis and portal hypertension in sarcoidosis. Hepatology 1997; 26: 55460.
  • 40
    Murphy JR, Sjogren MH, Kikendall JW, Peura DA, Goodman Z. Small bile duct abnormalities in sarcoidosis. J. Clin. Gatroenterol. 1990; 12: 55561.
  • 41
    Takemura T, Matsui Y, Saiki S, Mikami R. Pulmonary vascular involvement in sarcoidosis; a report of 40 autopsy cases. Hum. Pathol. 1992; 23: 121623.
  • 42
    Kapelman B, Schaffner F. The natural history of primary biliary cirrhosis. Sem. Liv. Dis. 1981; 1: 27381.
  • 43
    Sherlock S. Primary biliary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterology 1959; 31: 574.
  • 44
    Rubin E, Schaffner F, Popper H. Primary biliary cirrhosis. Chronic non suppurative destructive cholangitis. Am. J. Pathol. 1965; 46: 387.
  • 45
    Lee YM, Kaplan MM. Primary sclerosing cholangitis. N. Engl. J. Med. 1995; 332: 92433.
  • 46
    Becker WF, Coleman WO. Surgical significance of abdominal sarcoidosis. Ann. Surg. 1961; 153: 987.
  • 47
    Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. Harrison's Principles of Internal Medicine 5th edn. New York: McGraw-Hill, 2001.
  • 48
    Johns CJ, MacGregor MI, Zackery JB et al. Extended experience in the long term corticosteroids treatment of pulmonary sarcoidosis. Ann. N. Y. Acad. Sci. 1976; 278: 72231.
  • 49
    Turiaf J, Johns CJ, Teirstein AS et al. The problem of the treatment of sarcoidosis: Report of the subcommittee on therapy. Ann. N. Y. Acad. Sci. 1976; 278: 74351.
  • 50
    Murray JF, Nadel YA, Mason RJ, Boushey HA. Textbook of Respiratory Medicine 3rd edn. Philadelphia: WB Saunders, 2000.
  • 51
    American Thoracic Society, European Respiratory Society and World Association of Sarcoidosis and Other Granulomatous Disorders, Statement on sarcoidosis. Am. J. Respir. Crit. Care Med. 1999; 160: 73655.