The aminopyrine breath test does not correlate with histologic disease severity in patients with cholestasis

To determine whether the aminopyrine breath test can be used to document the presence of cirrhosis in patients with cholestatic liver disease, 19 patients (13 primary biliary cirrhosis, 4 sclerosing cholangitis and 2 chronic extrahepatic bile duct obstruction) underwent clinical and biochemical evaluations, liver biopsies and an aminopyrine breath test. Results were compared with those in 10 patients with biopsy-proven chronic active hepatitis with bridging and/or cirrhosis and in 22 healthy subjects. The aminopyrine breath test results in the 10 cholestatic patients with cirrhosis were not significantly different from the results in precirrhotic cholestatic patients (mean +/- S.D., 11.2 +/- 5.0 vs. 11.6 +/- 2.8% dose per 2 hr, p greater than 0.05) or healthy subjects (11.5 +/- 2.9% dose per 2 hr). In contrast, the results in the patients with chronic hepatitis were markedly depressed (3.2 +/- 1.9% dose per 2 hr, p less than 0.05). The aminopyrine breath test results did not correlate with results of conventional liver function tests in the cholestatic patients. These results demonstrate that the aminopyrine breath test is not clinically useful in identifying the presence of cirrhosis in patients with cholestatic liver disease, and provide further evidence that decreased microsomal enzyme function is a late feature of cholestatic liver disease.     

The occurrence of orcein-positive hepatocellular material in various liver diseases.

Liver specimens from 103 patients with various hepatic diseases and from 297 consecutive liver biopsies examined routinely were stained with orcein after oxidation of the tissue sections with potassium permanganate. Orcein-positive dark brown cytoplasmic material could be demonstrated in 27 cases with long-standing cholestasis. These patients had either primary biliary cirrhosis, the cholestatic liver disease of ulcerative colitis or chronic active hepatitis, advanced alcoholic cirrhosis or secondary biliary cirrhosis due to extrahepatic biliary obstruction. Orcein-positive material could not be demonstrated in congenital disorders of bilirubin metabolism or in hemochromatosis. Similarly, it could not be found in acute, toxic, alcoholic or chronic persistent hepatitis.     

Hepatobiliary complications in chronic pancreatitis.

Thirty nine patients undergoing surgery for chronic pancreatitis were investigated for evidence of hepatobiliary disease. In addition to pre-operative assessment by liver function tests, ultrasound, ERCP (in 33) and percutaneous transhepatic cholangiography (in five), all had peroperative liver biopsy. Common bile duct stenosis was diagnosed in 16 (62%) of the 26 patients with successful cholangiography. Features of extrahepatic biliary obstruction were found on biopsy in 11 patients, three of whom showed features of secondary sclerosing cholangitis. No patients had secondary biliary cirrhosis. Three had parenchymal liver disease (cirrhosis, resolving hepatitis and alcoholic hepatitis respectively) and two others had features suggestive of previous alcohol-induced injury. Five (83%) of the patients with clinical jaundice had biopsy features of extrahepatic biliary obstruction, as did eight (67%) with alkaline phosphatase above twice normal and seven (44%) with radiological common bile duct stenosis. Neither alkaline phosphatase rise, nor common bile duct stenosis alone or in combination, were a reliable indication of the need for biliary enteric bypass surgery. Pre-operative liver biopsy may be a valuable adjunct in the assessment of such patients.     

Drug- and chemical-induced cholestasis

Cholestasis resulting from drugs is an increasingly recognized cause of liver disease. It produces a broad clinical-pathologic spectrum of injury that includes simple jaundice, cholestatic hepatitis, and bile duct injury that can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis. Although the risk of drug-induced cholestasis leading to a fatal outcome is quite rare, knowledge and recognition of the various forms of cholestatic injury assumes an importance whenever clinicians are confronted with jaundice or other manifestations of liver disease in patients receiving medicinal or chemical agents.     

Inappropriate expression of blood group antigens on biliary and colonic epithelia in primary sclerosing cholangitis.

The distribution of carbohydrate antigens of the ABO, Lewis, and Kell systems was examined in biliary and colonic epithelial of 11 patients with primary sclerosing cholangitis (PSC) using a panel of 11 monoclonal antibodies. Controls consisted of 27 liver biopsy specimens (11 normal, six alcoholic liver disease, five extrahepatic obstruction, and five primary biliary cirrhosis) and 24 colonic biopsy specimens (six normal, four Crohn's disease, and 14 ulcerative colitis). There was inappropriate staining with anti-A (four of six, 66%) and anti-B (nine of 11, 81%) in biliary epithelium of PSC patients compared with normal and disease controls. Expression of Lewis antigens was increased in patients with cholestatic liver disease. Ninety one per cent of PSC patients showed a similar pattern of inappropriate staining by anti-A and anti-B antibodies in colonic epithelium compared with 33% of normal and 42% of inflammatory bowel disease controls. There is inappropriate expression of A and B carbohydrate antigens in biliary and colonic epithelium in PSC. Whether these oncofetal antigens are implicated in the pathogenesis of this condition is discussed.     

Benign familial recurrent intrahepatic cholestasis

Three new cases of benign familial recurrent intrahepatic cholestasis in a brother, sister, and mother are reported. These cases emphasize the familial nature of the disorder and the characteristic clinical findings of recurrent attacks, cholestatic jaundice, pruritus with increases in the serum bilirubin, and increased alkaline phosphatase. A normal extrahepatic biliary tree was shown by dye studies, and liver biopsy showed central lobular cholestasis without any inflammation or necrosis. Liver function tests were normal between attacks. This condition must be differentiated from extrahepatic obstruction, parenchymal liver disease, drug-induced cholestatic disease, and other familial types of jaundice.     

Selection criteria and decisions in 375 patients with liver disease,considered for liver transplantation during 1977–1985

ABSTRACT— We performed a prospective study on 375 patients with liver disease, 60% female, for whom orthotopic liver transplantation (OLT) was considered during 1977–1985. Fifty-four per cent had cirrhosis, 8.5% congenital/hereditary disorders, 25% malignant tumour, 6% benign tumour, 2% Budd-Chiari syndrome, 1.5% acute hepatic failure, 3% other diagnoses, and 10% were under 15 years of age. As of July Ist, 1985, 99 patients (47 chronic active/inactive cirrhosis (CAC/CIC), 28 primary biliary cirrhosis (PBC), five hepatocellular carcinoma (HCC), 19 other diagnoses) were accepted for OLT (median age 40 years, 10% under age 15). By that date, 45 patients (median age 42), had had an OLT (20 CAC/CIC, 15 PBC, three biliary atresia, two HCC, five other diagnoses). Fifty-four per cent (201 patients) were rejected for transplantation. The primary reasons for rejection were: no indication (11%), age (5%), other surgical procedures possible (3%), severe liver failure (14%), extrahepatic spread of liver tumour (11%), cardiovascular or pulmonary problems (2%), severe hepatic bone disease (1%), and miscellaneous (7%). Thirty per cent of the patients with CAC/CIC, 38% with PBC, 88% with HCC and 71% with biliary atresia were rejected. In the CAC/CIC, PBC and biliary atresia patients severe liver failure was the most frequent reason for rejection (62%, 50% and 60%, respectively). In HCC, extrahepatic tumour spread was the most frequent reason (72%) for rejection. In this category only two patients (7%) ultimately underwent liver transplantation.     

Selection criteria and decisions in 375 patients with liver disease, considered for liver transplantation during 1977-1985

We performed a prospective study on 375 patients with liver disease, 60% female, for whom orthotopic liver transplantation (OLT) was considered during 1977-1985. Fifty-four per cent had cirrhosis, 8.5% congenital/hereditary disorders, 25% malignant tumour, 6% benign tumour, 2% Budd-Chiari syndrome, 1.5% acute hepatic failure, 3% other diagnoses, and 10% were under 15 years of age. As of July 1st, 1985, 99 patients (47 chronic active/inactive cirrhosis (CAC/CIC), 28 primary biliary cirrhosis (PBC), five hepatocellular carcinoma (HCC), 19 other diagnoses) were accepted for OLT (median age 40 years, 10% under age 15). By that date, 45 patients (median age 42), had had an OLT (20 CAC/CIC, 15 PBC, three biliary atresia, two HCC, five other diagnoses). Fifty-four per cent (201 patients) were rejected for transplantation. The primary reasons for rejection were: no indication (11%), age (5%), other surgical procedures possible (3%), severe liver failure (14%), extrahepatic spread of liver tumour (11%), cardiovascular or pulmonary problems (2%), severe hepatic bone disease (1%), and miscellaneous (7%). Thirty per cent of the patients with CAC/CIC, 38% with PBC, 88% with HCC and 71% with biliary atresia were rejected. In the CAC/CIC, PBC and biliary atresia patients severe liver failure was the most frequent reason for rejection (62%, 50% and 60%, respectively). In HCC, extrahepatic tumour spread was the most frequent reason (72%) for rejection. In this category only two patients (7%) ultimately underwent liver transplantation.     

Immunocytochemical studies on cholestatic factor in human liver with or without cholestasis

ABSTRACT— The localization of the cholestatic factor (CF) was immunocylochemically investigated in liver biopsy specimens obtained from patients with various liver diseases. CF was detected in seven of nine patients with drug-induced liver injury, three of four with acute viral hepatitis, three of five with alcoholic liver injury and in the two patients with autoimmune hepatitis. Fourteen of these 15 CF-positive patients had jaundice in their clinical courses. CF was stained diffusely in the cytoplasm of hepatocytes throughout the lobules in a granular pattern. Electron-microscopically, it was localized on the ribosomes and polysomes as well as on the filamentous structures around the bile canaliculi. However, CF was not detected in liver specimens from normal controls and patients with primary biliary cirrhosis and extrahepatic biliary obstruction. These findings suggest that CF plays an important role in intrahepatic cholestasis in various liver diseases.     

Occurrence of an abnormal lipoprotein in patients with liver disease

An abnormal lipoprotein, containing a high proportion of unesterified cholesterol and phospholipid, has previously been described as occurring in the serum of patients with obstructive jaundice, and has been called lipoprotein X. Using an immunoelectrophoretic method for the detection of lipoprotein X in serum, the sera of 97 patients with liver disease have been screened and the associated biochemical features measured.

Lipoprotein X was found in 45% of cases of liver disease with cholestatic features, and was not detected in cases of liver disease without cholestasis. The incidence of lipoprotein X in different causes of cholestatis varied, and while it was commonest in cases of extrahepatic obstruction of recent onset, occurring in 75% of cases, it was also found in primary biliary cirrhosis in 48% of cases, and in cholestatic hepatitis, less commonly.

The cause of the appearance of lipoprotein X is unknown, but analysis of associated biochemical features suggested a relationship to physical biliary obstruction rather than a derangement of liver cell function.

     

LIVER INVOLVEMENT IN PRIMARY SJOGREN'S SYNDROME

Three hundred patients with primary Sjögren's syndrome(pSS) were investigated for liver involvement using clinical,biochemical, immunological and histological data. Seven percent of patients showed evidence of liver disease eithersubclinical (2%) or asymptomatic (5%) with elevated liver enzymesIn 6.6 % of patients antimitochondrial antibodies (AMA) weredetected by immunofluorescence and 27% of pSS patients showedantibodies to pyruvate dehydrogenase (a-PDH) using ELISA. AMA-positivepatients were further investigated with transcutaneous liverbiopsy. Ninety-two per cent of patients with AMA showed liverinvolvement with features of chronic cholangitis similar tostage I primary biliary cirrhosis It is concluded that liverinvolvement in pSS patients is rare and subclinical with histologicalfeatures predominantly of stage I primary biliary cirrhosisAMA is the most sensitive indicator of underlying liver pathologyin pSS patients KEY WORDS: Sjögren's syndrome, Antimitochondrial antibodies, Primary biliary cirrhosis     

Familial intrahepatic cholestatic cirrhosis in young adults

Two siblings with intrahepatic cholestatic cirrhosis and their brother, who had a potentially related disease at the time of accidental death, are presented. The onset of disease occurred during adolescence in all 3 cases. The initial sign was mild jaundice or portal hypertension. There was no abnormality in the countenance, cardiovascular system, or vertebral column. Except for the brother who died from an accident, jaundice gradually increased. Death followed due to cirrhosis. Liver biopsy specimens of these 2 patients showed diminution of interlobular bile ducts with no significant cholangitis. At autopsy, the livers of the 2 patients showed biliary cirrhosis without extrahepatic biliary obstruction. In both cases there was an accessory lobe on the right hepatic lobe. Histologically, septal bile ducts showed pronounced papillary proliferations of the epithelium; there was also a decrease in the number of small interlobular bile ducts. Excess copper accumulation in the liver was ascertained. It is suggested that the disease in the 2 autopsied cases is intrahepatic cholestatic cirrhosis due to hypoplasia of the intrahepatic biliary trees.     

Drug- and chemical-induced cholestasis

Cholestasis caused by medicinal and chemical agents is an increasingly well-recognized cause of liver disease. Clinical drug-induced cholestatic syndromes producing jaundice and bile duct injury can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis, among others. This article updates the various forms of drug-induced cholestasis, focusing on the clinicopathologic features of this form of hepatic injury and on the known or putative mechanisms by which drugs and chemicals lead to cholestasis.     

CHOLESTASIS IN ACUTE ALCOHOLIC LIVER DISEASE

10 of a series of 108 patients with alcoholic liver disease presented with cholestasis associated with non-cirrhotic alcoholic liver disease and without evidence of extrahepatic biliary obstruction. In 7 patients liver histology and the associated conditions presenting as cholestasis were heterogeneous. However, in 3 patients who had been drinking excessively before cholestatic jaundice developed, cholestasis was a major feature of liver histology. The term acute alcoholic cholestasis is suggested for this apparently distinct syndrome of cholestatic jaundice in the absence of hepatitis.     

Overlap syndromes from pediatrics to adulthood

Abstract   Overlap syndromes are autoimmune conditions with mixed immunological, clinical and histological features. The most frequent overlaps are between primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH), and between AIH and sclerosing cholangitis (SC). True AIH/PBC overlap syndrome is rare and characterized by elevation of transaminases and immunoglobulin G (IgG), positive anti-smooth muscle antibodies and a liver biopsy showing interface hepatitis as well as changes typical of PBC. These patients respond to immunosuppressive treatment that must be given promptly, to avoid progression to liver failure. The so-called 'autoimmune cholangitis' defines a small group of patients with cholestatic and histological features of PBC but negative for anti-mitochondrial antibody (AMA) and positive for PBC-specific anti-nuclear antibody (ANA). The positivity for ANA in these patients is a consequence of the AMA negativity, since AMA masks ANA on immunofluorescence. These patients' clinical course and response to treatment resemble that of classical PBC. AIH/ASC overlap syndrome is characterised by elevated levels of IgG and circulating autoantibodies, including ANA, SMA and atypical perinuclear anti-neutrophil cytoplasmic antibody, in association with cholangiographic changes typical of SC. This condition affects in particular children and young adults and may represent the early stage of adult primary SC. The parenchymal liver inflammation responds satisfactorily to immunosuppression, while the bile duct damage may progress despite treatment.     

Is routine cholangiography useful in men with suspected primary biliary cirrhosis?

The aim of this study was to assess the diagnostic value of cholangiography in men with chronic cholestasis and positive antimitochondrial antibody (AMA) titers who were suspected of having primary biliary cirrhosis (PBC). The authors reviewed retrospectively the records of men who had positive AMA titers over a 16-month period to determine the results of cholangiography. They also reviewed the records of 102 patients with primary sclerosing cholangitis (PSC) from 1989 to 1995 who had undergone cholangiography and testing for AMA. Of 35 men with positive tests for serum AMA, 12 of these patients were referred for cholangiography (11 endoscopic and 1 transhepatic). All completed cholangiograms were normal. A diagnosis of PBC was made in nine patients and atypical autoimmune hepatitis in one. Conversely, only two PSC patients had positive AMA titers (1:20 and 1:80). Both of these patients had coexisting inflammatory bowel disease and cholangiograms diagnostic of PSC. Cholangiography was negative in the male patients with positive AMA titers who were suspected of having PBC. In men with cholestatic liver biochemistries and strongly positive AMA titers, especially in the absence of associated inflammatory bowel disease, routine cholangiography does not add to the diagnostic evaluation.     

Demonstration of an intracellular copper-binding protein by orcein staining in long-standing cholestatic liver diseases.

Liver biopsies from eight patients with primary biliary cirrhosis, two with chronic active hepatitis of a cholestatic form, three with long-standing alcoholic liver cirrhosis, and one with extrahepatic biliary obstruction were studied. In each case dark brown cytoplasmic material was seen after staining of the tissue sections with Shikata's orcein method. In exactly the same cellular and subcellular locations as the orcein-positive material, and with morphologically equal granules, two different ordinary staining methods for copper (rubeanic acid and Mallory-Parker's haematoxylin) gave positive reactions. The earlier histochemical findings have revealed the protein nature and high sulphydryl content of the orcein-positive material. Its close association with copper in liver sections suggests its copper-binding nature and indicates that a common copper-protein complex accumulates in the cytoplasm of liver cells during longstanding cholestasis in biliary diseases of various pathogenetic origin.     

LP-X in cholestasis.

Extrahepatic and intrahepatic biliary obstruction of different etiology were studied in 62 patients, who were investigated for the presence of lipoprotein X (Lp-X). It was found present in 19 of 20 cholestasis by lithiasis, in all three primary biliary cirrhosis patients, in 2 of 4 cirrhosis, in 5 of 13 hepatitis, in all three benign recurrent intrahepatic cholestasis and in 1 of 2 recurrent juandice of pregnancy. It was found in a Dubin Johnson. Lp-X disappeared in 4 patients within two weeks after relief of the obstruction. It was found in patients with cholestatic hepatitis during the first week of jaundice. It was found in the first 48 hours in three patients with cholestasis by lithiasis. Lp-X does not help in differential diagnosis between extrahepatic and intrahepatic biliary obstruction, but the time of its appearance could contribute to it in some cases. A word of caution is raised in indicating surgery in a cholestatic patient without the presence of Lp-X.     

Medical and endoscopic therapy of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease mainly affecting young male patients. PSC is characterised by chronic inflammation and fibrotic strictures of the intra- and extrahepatic biliary system, which eventually lead to cholestasis and biliary cirrhosis. However, the clinical course remains very variable. As the aetiology remains unknown, the development of a causative treatment is challenging and today no specific medical therapy is available. Ursodeoxycholic acid has been widely used for the treatment of PSC, but improved only biochemistry and/or symptoms in low- or medium dosages and is probably harmful in higher dosages. Other drugs such as immunosuppressive, antifibrotic or antibiotic agents have not been proven to be effective in large clinical trials. The endoscopic therapy encompasses balloon-dilatation and/or stenting of strictures, relieves clinical symptoms and improves a cholestatic enzyme profile. However, endoscopic therapy is limited to patients in advanced stages of PSC with biliary obstruction.     

Antimitochondrial antibodies in patients with chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) and primary biliary cirrhosis (PBC) have many clinical and laboratory features in common. These include scleroderma or lupus erythematosus-like skin lesions, a Sj?gren-like sicca syndrome, cholestatic liver disease and a variety of serological autoimmune phenomena. Furthermore, liver histology in both diseases is characterized by lymphocytic infiltration of the portal fields and destruction of small bile ducts. We investigated whether there were also parallels between both diseases in incidence and characteristics of antimitochondrial (AMA) and other autoantibodies. Sera from patients with cGVHD (n = 11, group 1) were examined by immunofluorescence (IFL) and immunoblot (IBL), and the results were compared with sera from patients without cGVHD (n = 21, group 2) and after autologous BMT (n = 16, group 3). In group 1 AMA was detected by IFL in one and by IBL in nine of 11 (81%) patients. Group 2 and 3 patients were AMA-negative by IFL and AMA positive by IBL in statistically lower incidence of 19% and 6% (p less than 0.001), respectively. cGVHD-associated AMA recognized a spectrum of mitochondrial proteins, the most frequent being molecules of 63/60 kD and 22 kD. Follow-up studies showed a temporal correlation between the emergence of AMA and the clinical occurrence of cGVHD. We conclude that patients with cGVHD have a high incidence of AMA similar to patients with PBC, but the reaction pattern of AMA differs between the diseases. The presence of AMA in cGVHD further emphasizes the concept that both diseases may have a related pathogenetic background.