Gut, 1982, 23, 417-421

Case reports

Chronic intrahepatic cholestasis due to sarcoidosisN M BASS*, A K BURROUGHSt, P J SCHEUER,D GERAINT JAMES, and SHEILA SHERLOCK

From The Departments of Medicine and Histopathology, Royal Free Hospital, and Department of Medicine,Royal Northern Hospital, London

SUMMARY Two West Indian patients with Kveim-biopsy proven sarcoidosis developed chroniccholestatic liver disease, clinically and biochemically similar to primary biliary cirrhosis. Liverhistology revealed multiple granulomas with reduction in bile ducts and, in one patient,progression to biliary cirrhosis. Portal hypertension was present in both patients leading to severevariceal haemorrhage in one. Mitochondrial antibody was negative in both patients and whenused in conjunction with the Kveim-Siltzbach skin test serves to differentiate chronic intrahepaticcholestasis secondary to sarcoidosis from primary biliary cirrhosis.

Hepatic involvement in sarcoidosis is common,consisting of multiple hepatic granulomas withoutclinically overt liver disease. Severe liver diseasefrom sarcoidosis is rare, manifesting as hepato-cellular failure and portal hypertension.' 2 Adistinctly rare form of presentation is that of chronicintrahepatic cholestasis, which may mimic primarybiliary cirrhosis. Attention was drawn to this variantof hepatic sarcoidosis by Rudzki et a13 who reportedits occurrence in five American black males.However, confirmatory Kveim biopsies andcholangiographic data were lacking in that series.We report chronic intrahepatic cholestasis in two

West Indians with chronic sarcoidosis confirmed byKveim-Siltzbach skin test biopsies and raised levelsof serum angiotensin converting enzyme (SACE).

Case reports

CASE I A 50-year-old West Indian woman from StVincent who had been living in the United Kingdomsince 1961 was first seen at the Royal Free Hospitalin October 1979 with persistent itching andjaundice.Abnormal liver function tests had first been noted

in 1968 when she was investigated for proteinura.' Present address: Gastrointestinal Research Unit. 1120 HSW, University ofCalifornia, San Francisco Medical Center. San Francisco, California 94143,USA.t Address for correspondence and reprint requests: Dr A K Burroughs,Department of Medicine, Royal Free Hospital and Medical School, PondStreet. Hampstead, London NW3 2QG, UK.Received for publication 1 September 1981

There were no physical abnormalities at that time,but the alkaline phosphatase and 5'-nucleotidasewere reportedly raised. The chest radiograph wasnormal, but a bone marrow biopsy showed multiplegranulomas. The Mantoux test, VDRL, brucellaagglutinins, Toxacara complement fixation test, andCasoni test were negative. The record of the Kveimtest performed elsewhere at that time wasunavailable.The proteinuria resolved spontaneously, but she

then developed iritis which was treated with steroidand atropine drops.

Pruritus began in 1970 and was initially inter-mittent. Liver disease became overt in 1976 whencholestatic jaundice and worsening pruritisdeveloped. Hepatomegaly was noted and a liverbiopsy showed portal inflammation and ductularproliferation, and a cluster of non-caseatinggranulomas. She was treated with antihistaminesonly. In May 1977 a laparotomy for persistentsymptoms revealed an enlarged, soft liver. Biopsyagain showed ductular proliferation but nogranulomas were seen on this occasion.On examination in October 1979 she had mild

jaundice and numerous excoriations. There were noxanthelasmas or other cutaneous markers of chronicliver disease. The liver and spleen were bothpalpable, 4 and 3 cm below the costal marginrespectively. Keloid formation was present in scars.There was no ascites. The heart, lungs, and nervoussystem were normal. Fundoscopy revealed evidenceof previous right uveitis.

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The full blood count was normal; the erythrocytesedimentation rate was 70 mm/h Westergren(normal <20), the alkaline phosphatase was 71KA/dl (normal 3-13), total bilirubin 43 ,mol/l(normal 3-17) (2.3 mg/100 ml (0.1-0.9)), aspartatetransaminase 39 IU/l (normal 5-15), albumin 32 g/l(normal 36-50), and the prothrombin time was 15seconds (control 13). Serum cholesterol level was6-7 mmol/l (normal 3-6.5) (260 mg/100 ml (140-250)). Hepatitis B surface antigen, antinuclearantibody, smooth-muscle antibody, and mito-chondrial antibody were negative. The VLDL waspositive (titre 1:4), the TPHA positive in a titre of1:1280 with a positive FTA (ABS). The cerebro-spinal fluid was normal. The patient had had yaws inchildhood. However, a full course of penicillin wasgiven in 1979. No change in the symptoms,serological or biochemical tests was noted aftertreatment or over subsequent months.The IgG was 28.5 g/l (normal 8-18), the IgA and

IgM were normal. The SACE level was raised to 83nmol/min/ml (normal 16-52) (2.22 mg/min/100 ml(0.45-1.39)). A percutaneous liver biopsy (Fig. 1)showed many epitheloid-cell granulomas through-out, both singly and in clusters. Some granulomascontained large multinucleated giant cells and therewas a variable degree of central necrosis. A fewcrystalline, birefringent inclusions were seen. Therewere irregular fibrous septa in associations with thegranulomas, but, although lobular architecture wasdistorted, cirrhosis was not evident. Bile ducts weremarkedly reduced in number. Abundant copper-associated protein was seen on orcein staining. Livercopper content was raised at 332 g/g dry liver(normal 5-55) as measured by neutron activationanalysis. Biopsy of the keloid scars did not revealsarcoid infiltration.A radiograph of the chest was normal but

pulmonary function studies showed a mildobstructive and restrictive defect. Serum andurinary calcium and phosphate were normal. AKveim-Siltzbach skin test biopsy was positive,providing sarcoid histology and indicative of activesarcoidosis. Endoscopy during retrogradepancreatography showed oesophageal varices anddemonstrated a normal pancreatic duct. Trans-hepatic percutaneous cholangiography showed anon-dilated biliary tree with no obstruction. Theintrahepatic bile ducts were tortuous and appearedstretched in places; this was compatible withdistortion of liver architecture but not withsclerosing cholangitis.The itching was relieved by cholestyramine and

on follow-up there have been no further problemsapart from increasing dyspnoea due to lung involve-ment. This necessitated the use of prednisolone,

Fig. 1 Case 1. Part ofa live biopsy showing coalescinggranulomas with a multinucleated giant cell (arrow),adjacent to liver parenchyma (below right). Haematoxylinand eosin, x 140.

which has not altered the liver function tests orrelieved itching when cholestyramine wastemporarily stopped.

CASE 2 A 46-year-old West Indian man, who hadbeen living in the United Kingdom since 1961, wasfirst seen at the Royal Free Hospital in March 1980with bleeding oesophageal varices.

In 1963 he experienced malaise with cough and aradiograph of the chest showed bilateral hilarlymphadenopathy. The Kveim-Siltzbach test waspositive and he was treated with steroids with a goodresponse. He developed jaundice, hepatomegaly,and generalised lymphadenopathy a year later, andliver biopsy showed multiple granulomas consistentwith a diagnosis of sarcoidosis. Steroid treatmentwas continued until 1972 and then withdrawn afterimprovement in his jaundice. A Kveim biopsy wasstill positive in 1970. In 1977 he presented withhaematemesis and melaena and large oesophagealvarices were seen on endoscopy. In 1979 he experi-enced itching with deepening jaundice, pale stools,and dark urine.

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Chronic intrahepatic cholestasis due to sarcoidosis

On endoscopic retrograde cholangiography, theintrahepatic biliary tree showed distortioncompatible with cirrhosis, with a normal undilatedextrahepatic biliary tree. The patient complained ofpain in the ankles in February 1980 and was noted tohave developed gross clubbing of fingers and toeswith typical radiographic changes of hypertrophicpulmonary osteoarthropathy. His limb pain wastreated with indomethacin but he returned in Marchwith bleeding varices seen on endoscopy.On admission, he was jaundiced, with clubbing,

excoriations, bilateral parotid enlargement, softcrepitations at both lung bases, a palpable liver 6 cmbelow the costal margin, a palpable spleen 3 cmbelow the costal margin, and minimal ascites. Theheart was normal, and apart from drowsiness andflapping tremor, the nervous system was normal.The haemoglobin was 10-2 g/dl, the white count

normal and platelet count 80x 109/l. The alkalinephosphatase was 38 KA/dl, aspartate transaminase76 IU/l, albumin 29 g/l, total bilirubin 455 ,umol/l(26.8 mg/100 ml (0.1-0.9)). The prothrombin timewas 15 seconds (control 13). Serum cholesterol wasnormal, and serum and urinary calcium andphosphate were normal. The VDRL, hepatitis Bsurface antigen, antinuclear antibody, smooth-muscle antibody, and mitochondrial antibodies werenegative. Immunoglobulins were all normal. TheSACE level was raised to 72 nmol/min/ml (1-93mg/min/100 ml). The radiograph of the chestshowed bilateral hilar lymph node enlargement andbilateral pulmonary infiltration. Splenoportographydemonstrated a large splenorenal collateral andhepatic and superior mesenteric arteriographyrevealed arterialisation of the intrahepatic portalvenous system with rapid retrograde portal flow. Atranshepatic sclerosis of the bleeding varices wassuccessfully achieved. The portogram revealed anextensive portal collateral circulation with largevarices. After the sclerosis, the patient made anuneventful recovery with resolution of fluidretention and portosystemic encephalopathy. Thecholestasis, however, has persisted. Liver biopsiestaken between 1964 and 1980 were reviewed, andshowed granulomas, abundant at first and laterscanty, and gradual development of cirrhosis ofbiliary pattern (Fig. 2). Granulomas contained giantcells, some with asteroid bodies, but no necrosis.

Bile ducts were strikingly reduced in numbers,ductular proliferation was a prominent feature, andmuch copper-associated protein was seen.

Discussion

The clinical spectrum of hepatic involvement insarcoidosis extends from asymptomatic granulo-

Fig. 2 Case 2. Cirrhosis of biliary type has developed, withductular proliferation in a perinodular zone ofoedematousconnective tissue. A small granuloma is seen within anodule. Haematoxylin and eosin, x 70.

matosis to overt hepatic disease manifested byhepatocellular failure or portal hypertension orcombinations of both.1 Intrahepatic cholestasis hasbeen reported as another rare manifestation oflong-standing hepatic sarcoidosis by Rudzki et al,3although confirmatory Kveim biopsies could not beperformed in their series of five young Americannegro males.The two cases reported here, both of whom had

the diagnosis of sarcoidosis confirmed on Kveimbiopsy, show many similarities to the casespreviously described. Both patients are immigrantWest Indians, a racial group sharing with Americanblacks an exceptionally high incidence ofsarcoidosis. Systemic granulomatous diseasepreceded the onset of cholestasis in both patients.This feature, together with the long natural historyof the disease (22 and 27 years in cases 1 and 2respectively, both of whom are still alive, and 10 to18 years in the series reported by Rudzki et a13),serves to differentiate the conditions of chronicintrahepatic cholestasis of sarcoidosis from primary

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biliary cirrhosis in which patients who usuallypresent with cholestasis thereafter survive for amean period of six to 11 years.5 6 An additionalpoint of note is the high male:female ratio incholestasis due to sarcoidosis, which contrasts withthe female preponderance of primary biliarycirrhosis.The most reliable means for differentiating

sarcoid cholestasis from primary biliary cirrhosis arethe Kveim-Siltzbach skin test and the mitochondrialantibody titre, and both cases in this report conformfully to these criteria needed to distinguish themfrom primary biliary cirrhosis. Other differentiatingfeatures include normal IgM levels (usually raised inprimary biliary cirrhosis) and histological features.7In primary biliary cirrhosis eccentric infiltrates ofplasma cells, lymphocytes, and eosinophils are seenin relation to damaged bile ducts. Granulomas arecommon, but are usually few in number and oftenpoorly defined. In sarcoidosis, on the other hand,bile duct damage, even when present, is lessconspicuous, while granulomas are abundant andwell-formed. The lesions are often clustered, andhealing may result in substantial scars. In spite ofthese differences, the two conditions are occasion-ally histologically similar, or even indistinguishable.Firm differentiation between sarcoidosis andprimary biliary cirrhosis may, on rare occasions,prove to be impossible and both conditions may,apparently, coexist. Both a positive Kveim test andlow titres of anti-mitochondrial antibody. werereported in one patient with mediastinal lymph nodeenlargement and chronic granulomatous biliarycirrhosis.8 Another patient has been described withintrahepatic cholestasis secondary to a chronicgranulomatous biliary cirrhosis histologically typicalof sarcoidosis, in whom both the Kveim test andmitochondrial antibodies were negative.9 Further-more, widespread granulomas suggestive ofsarcoidosis have been found in the lungs, lymphnodes and spleens of patients with serologicallyproven primary biliary cirrhosis, and negativeKveim-Siltzbach tests. 10 SACE levels wereincreased in both our patients, and, although SACEmeasurement is not a specific test for sarcoidosis,raised levels help to corroborate the diagnosis of thisdisease.11 12

Previously reported cases of cholestatic jaundiceassociated with sarcoidosis have also mimickedprimary biliary cirrhosis in the development ofhypercholesterolaemia and skin xanthomas.3 13-15 Incontrast, case 1 in this report had only mildly raisedserum cholesterol, while in case .2, cholesterol levelswere normal. These findings may reflect a relativelyearly phase of disease in case 1 and a late phase(during which cholesterol levels may fall) in case 2.

Another interesting feature in case 2 was thepresence of hypertrophic 'pulmonary' osteoarthro-pathy. Clubbing and hypertrophic osteoarthropathyare not features of sarcoidosis. However, clubbingmay occur in most forms of liver disease, hyper-trophic osteoarthropathy being more frequentlyassociated with chronic cholestatic liver disease. 16The coexistence of portal hypertension with intra-

hepatic cholestasis of sarcoidosis was established inboth cases; varices were present in both andbleeding presented a major problem in case 2.Portal hypertension also developed in 4/5 of thecases reported by Rudzki et al.3 Portal hypertensionwould thus seem to accompany this syndromefrequently, although the converse statement doesnot hold true.1 It is also apparent that the naturalhistory of the condition is one of progression tocirrhosis of a 'biliary' pattern (case 2), althoughportal hypertension may antedate this appearanceon liver biopsy as in other forms of biliary disease asin case 1. It thus seems likely that, in chronicintrahepatic cholestasis of sarcoidosis, the sameprocess of granulomatous and subsequent fibrousdestruction of bile ducts leads to compression anddestruction of portal venous radicles, with earlyevolution of portal hypertension. An additionalcontribution towards the development of portalhypertension in sarcoidosis may result fromincreased portal blood flow secondary to theformation of intrahepatic arteriovenous shunts inthe regions of granulomas.' This proposal issupported by the findings in case 1 of an arterialisedintrahepatic portal system with hepatofugal portalblood flow seen during hepatic arteriography.

Sarcoidosis may produce jaundice by othermechanisms than intrahepatic cholestasis. Increasedsplenic red blood cell destruction, hepatocellularfailure, and obstruction of the extrahepatic bileducts by granulomatous hepatic hilar lymph nodeshave been proposed as possible mechanismsproducing jaundice. 1 There was no evidence ofexcessive haemolysis in either of the two patients,and non-obstructed biliary trees were demonstratedin both by cholangiography. Case 2 had additionalfeatures of hepatocellular failure, but these were notsufficient to explain the predominantly cholestasticclinical picture.Long-term benefit from corticosteroid therapy in

hepatic sarcoidosis is difficult to assess because ofgreat variations in both the natural history of thedisease and the stage of the disease at the time ofinstituting therapy. In case 1, no short-term benefitfrom steroids on liver function tests was evident.Cholestyramine was effective in relieving pruritis,but steroids alone did not affect this symptom. Incase 2, overt liver disease appeared to develop

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Chronic intrahepatic cholestasis due to sarcoidosis 421

during steroid therapy, although later progressionoccurred after steroids were stomped. These findingsbear out earlier observations' that no consistentclinical or pathological effect of corticosteroids isdemonstrable in patients with advanced hepaticsarcoidosis.

We thank the Department of Histopathology atWycombe General Hospital for providing histologyspecimens and Dr Roger Bird for performing theSACE estimations.

References

1 Maddrey WC, Johns CJ, Boitnott JK, Iber FL.Sarcoidosis and chronic hepatic disease: a clinical andpathologic study of 20 patients. Medicine (Balt) 1970;49: 375-95.

2 Porter GH. Hepatic sarcoidosis. A cause of portalhypertension and liver failure. Arch Intern Med 1961;108: 483-95.

3 Rudzki C, Ishak KG, Zimmerman HJ. Chronic intra-hepatic cholestasis of sarcoidosis. Am J Med 1975; 59:373-87.

4 Siltzbach LE, James DG, Neville E, et al. Course andprognosis of sarcoidosis around the world. Am J Med1974; 57: 847-52.

5 Schapiro JM, Smith H, Schaffner P. Serum bilirubin: aprognostic factor in primary biliary cirrhosis. Gut 1979;20: 137-40.

6 Roll J, Boyer J, Klatskin G. Long term survival ofasymptomatic and symptomatic patients with primarybiliary cirrhosis. Gastroenterology (Abstract) 1980; 79:1050.

7 Sherlock S, Scheuer PJ. The presentation and diagnosisof 100 patients with primary biliary cirrhosis. N Engl JMed 1973; 289: 674-8.

8 Karlish AJ, Thompson RPH, Williams R. A case ofsarcoidosis and primary biliary cirrhosis. Lancet 1969;2: 599.

9 Thomas E, Micci D. Chronic intrahepatic cholestasiswith granulomas and biliary cirrhosis. J Am Med Ass1977; 238: 337-8.

10 Stanley NN, Fox RA, Whimster WF, Sherlock S,James DG. Primary biliary cirrhosis or sarcoidosis - orboth. N Engl J Med 1972; 287: 1282-4.

11 Studdy P, Bird R, James DG, Sherlock S. Serumangiotensin-converting enzyme (SACE) in sarcoidosisand other granulomatous disorders. Lancet 1978; 2:1331-4.

12 De Remee RA, Rohrbach MS. Serum angio-tensin-converting enzyme activity in evaluating theclinical cause of sarcoidosis. Ann Intern Med 1980; 92:361-5.

13 Foxworthy DT, Freeman S. Biliary cirrhosis withcutaneous xanthomatoses due to sarcoidosis.Treatment with low cholesterol diet, ACTH andcortisone. J Lab Clin Med 1952; 40: 799.

14 Holtzman IN. Sarcoidosis followed by biliary cirrhosisand xanthomatoses. NY J Med 1961; 61: 1757-64.

15 Branson JH, Park JH. Sarcoidosis - hepatic involve-ment: presentation of case with fatal liver involvement,including autopsy findings and review of evidence forsarcoid involvement of liver as found in literature. AnnIntern Med 1954; 40: 111-45.

16 Epstein 0, Ajdukiewicz AB, Dick R, Sherlock S.Hypertrophic hepatic osteoarthropathy. Am J Med1980; 67: 88-97.

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