Jurgen Ludwig

Chronic hepatitis. An update on terminology and reporting.

The terms chronic active hepatitis (CAH), chronic persistent hepatitis (CpH), and chronic lobular hepatitis (CLH) have become obsolete, and their use without further specifications should be discontinued. This recommendation has become necessary because these names have changed from descriptive terms, intended for grading, to terms that are used either as morphologic diagnoses or disease designations or both, depending on individual preferences. Because this practice has caused serious misunderstandings, many authors and two international groups have recommended the use of a clear etiologic terminology. For the reporting practice of pathologists, we recommend that the pathologist routinely sign out biopsy samples with features of chronic hepatitis by indicating etiology, grade, and stage. An example would be autoimmune hepatitis, severe, stage 3. The stage in this case would indicate the presence of well-developed septal fibrosis but no nodular regeneration. Obviously, for the etiologic diagnosis, morphologic findings must be integrated with clinical and laboratory data. If this information is not available, clear morphologic diagnoses should be reported. Thus, instead of CPH, the diagnosis should be portal hepatitis, cause undetermined. This reporting practice eliminates ambiguous terminology and avoids the risk of inappropriate treatment as might occur, for example, when a term such as CAH is used to describe Wilsons disease and is misunderstood to mean autoimmune hepatitis. For a transitional period and to facilitate relearning, the terms CAH, CPH, and CLH can be reported in parentheses behind the etiologic diagnosis.

Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).

Staging of liver biopsy specimens from patients with chronic non-suppurative destructive cholangitis (CNDC or syndrome of primary biliary cirrhosis) has become an important part of clinical studies that are currently done in many centers. Therefore, staging methods should be based on uniform criteria that are applicable to all specimens and are easily reproducible. Most pathologists staging CNDC use the system proposed by Scheuer and modified slightly by Popper and Schaffner; and generally these methods serve well. But the features relied upon as characteristic of the earlier phases of CNDC (namely, inflammatory destruction of intrahepatic bile ducts and proliferation of ductules) are not always present in biopsy specimens from early cases, and occasionally they coexist with more advanced lesions, such as bridging necrosis. We suggest a new staging system, based on our experience with 219 individual biopsy specimens from 101 patients with well established CNDC. Our proposed criteria are: stage I — portal hepatitis; stage II — periportal hepatitis; stage III — septal fibrosis or bridging necrosis, or both; and stage IV — cirrhosis. In most instances, we found these features easy to recognize, and one or another of them was always present. Intra-observer and interobserver variations were small. Experience with the proposed staging system indicates that stages III and IV are encountered 3 or 4 times as commonly as stages I and II. Incidence of inflammatory bile duct destruction seemed to vary little from stages I to II. Cholestasis and positive copper stains were most common in stages III and IV. Die histologischen Stadien der chronisch-destruierenden, nichteitrigen Cholangitis (CNDC oder Syndrom der primÄren biliÄren Zirrhose) müssen genau bestimmt werden, um (1) den Krankheitsablauf zu verfolgen und damit — in weiten Grenzen — die Lebenserwartung einzelner Patienten zu bestimmen, und (2) um den Erfolg von Behandlungsversuchen an Patientengruppen zu bewerten. Die histologischen Stadien der CNDC werden meist nach der Methode von Scheuer oder, in leichter Abwandlung, nach der von Popper und Schaffner bestimmt. Diese Methoden funktionieren ausgezeichnet, wenn die für die Frühstadien namengebenden VerÄnderungen (entzündliche Gallengangszerstörung und Proliferation der GallenkanÄlchen) im PrÄparat sichtbar sind. Leider ist das in manchen FÄllen nicht so, oder die histologischen VerÄnderungen, die die Frühstadien kennzeichnen sollen, kommen gemeinsam mit den Merkmalen spÄterer Stadien vor. Auf Grund unserer Erfahrungen mit 219 LeberbiopsieprÄparaten von 101 Patienten mit nachgewiesener CNDC möchten wir eine neue Stadieneinteilung vorschlagen. Die Einteilungskriterien sind: Stadium I — portale Hepatitis; Stadium II — periportale Hepatitis; Stadium III — septale Fibrose oder Brückennekrose, oder beides; und Stadium IV — Zirrhose. Die namengebenden histologischen VerÄnderungen waren leicht zu erkennen und in jedem PrÄparat vorhanden. Die Einteilungsergebnisse waren gut reproduzierbar, sowohl vom gleichen Untersucher als auch von 2 verschiedenen Untersuchern. Die Stadien III und IV fanden sich in unserem Material drei- bis viermal hÄufiger als die Stadien I und II. Entzündliche Gallengangszerstörung fand sich in den Stadien I und II mit etwa gleicher HÄufigkeit. FÄrbbares Gallen- und Kupferpigment war am hÄufigsten in den Stadien III und IV.

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis

BACKGROUND/AIMS A double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) was conducted in 180 patients with primary biliary cirrhosis (PBC) to define the efficacy and safety of UDCA. Efficacy was assessed by time to treatment failure defined as death; liver transplantation; histological progression; development of varices, ascites, or encephalopathy; doubling of total serum bilirubin levels; progression of fatigue or pruritus; drug toxicity; or voluntary withdrawal. METHODS Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography, upper endoscopy, and liver biopsy at entry as well as at 2 years. Liver chemistries were determined every 3 months. RESULTS In patients receiving UDCA, treatment failure was delayed compared with the placebo-treated group (P = 0.0003, log rank test). Seven patients receiving UDCA died or required transplantation compared with 12 in the placebo group (P = 0.18). No patients discontinued UDCA because of side effects of toxicity. CONCLUSIONS UDCA was extraordinarily safe and well tolerated, and its use was associated with delayed progression of the disease as defined in this study. However, the lack of effects on symptoms, histology, and the need for liver transplantation or survival indicate that further evaluation is necessary to determine the ultimate role of UDCA in the treatment of PBC.

Hepatic steatosis as a potential risk factor for major hepatic resection

Hepatic steatosis is a recognized risk factor for primary nonfunction of hepatic allografts, but the effect of steatosis on postoperative recovery after major liver resection is unknown. Our aim was to determine if hepatic steatosis is associated with increased perioperative morbidity and mortality in patients undergoing major resection. A retrospective review of medical records of 13 5 patients who had undergone major hepatic resection from 1990 to 1993 was performed. Histopathology of the hepatic parenchyma at the resection margin was reviewed for the presence of macroor microvesicular steatosis. The extent of steatosis was graded as none (group l), mild with less than 30% hepatocytes involved (group 2), or moderate-to-severe with 30% or more hepatocytes involved (group 3). Outcome of patients was correlated with extent of steatosis. Patients with moderate-to-severe steatosis were obese (body mass index = 25.8 +-2 0.5 vs. 26.5 t 1.0+-. 33.4 +2.9; P <0.05 groups 1,2, and 3, respectively) and had an increased serum bilirubin concentration preoperatively. Hepatectomy required a longer operative time for group 3 (290 +-2 9 minutes vs. 287 +13 minutes vs. 35.5 +24 minutes; P <0.05 groups 1,2, and 3, respectively). Likelihood of blood transfusion was 5 1% in group l,S2 % in group 2, and 7 1% in group 3. Mortality was 14% in group 3 vs. 3% in group 1, and 7% in group 2; and liver failure occurred in 14% of patients in group 3 compared to 4% and 9% in groups 1 and 2, respectively. Patients in group 3 also had increased post-operative bilirubin levels compared to preoperative values. Moderate-to-severe hepatic steatosis may be associated with increased perioperative morbidity and mortality, and preoperative identification of steatosis warrants caution prior to major resection.

Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

We describe six patients with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). From 1990 to 2001, we treated 82 patients with NASH and observed six patients (three men and three women, aged 56-72 years) in this group who were referred with HCC or developed the complication during follow-up. In five of these six patients, NASH was associated with obesity (cases 3, 4 and 5), hyperlipidemia (case 5), or diabetes mellitus (cases 1, 3 and 6). We confirmed the presence of HCC by ultrasonography-guided tumor biopsy or surgery except in case 3 where we diagnosed the tumor by ultrasonography, computed tomography and selective hepatic arteriography. The carcinomas measured 1.5-6.0 cm in diameter and three were well differentiated. When HCC was diagnosed, cirrhosis was present in all instances. Four of the six tumor patients also had esophageal varices but only one patient had a history of variceal bleeding and ascites. Treatment of HCC consisted of surgery (cases 1 and 5), transcatheter arterial embolization or infusion and/or percutaneous ethanol injection (cases 2, 3, 4, and 6). In patients with NASH cirrhosis, the development of treatable HCC is sufficiently common to warrant regular screening for this grave complication.

Current concepts. Primary sclerosing cholangitis.

OBJECTIVE To describe primary sclerosing cholangitis (PSC) and its associated complications, as well as medical and surgical treatment. DESIGN A review of PSC and its associated etiopathologic factors is presented; numerous studies of agents that are used to treat patients with PSC are discussed. RESULTS PSC, a slowly progressive disease that often involves autoimmune damage to the biliary tree, is frequently associated with inflammatory bowel disease, usually chronic ulcerative colitis. Long-term follow-up of patients with PSC has revealed a high incidence of colon cancer and bile duct cancer, both of which are most likely related to the chronic inflammation involving these two organs. Although PSC is an unusual disease, it is now diagnosed with approximately the same frequency as is primary biliary cirrhosis. The histopathologic evolution of PSC results in irreversible damage to bile ducts, which ultimately leads to cholestasis, cirrhosis, liver failure, and premature death from liver failure unless liver transplantation is performed. Therefore, the best chance of achieving success is to treat patients with early-stage disease rather than those with irreversible end-stage cirrhotic disease. Although several medical therapies for PSC have been evaluated, only D-penicillamine, cyclosporine, methotrexate, and, most recently, ursodeoxycholic acid have been studied in controlled clinical trials. Furthermore, several surgical therapies for PSC and its associated complications have been assessed. CONCLUSION Currently, no therapy achieves a complete clinical, biochemical, or histologic remission in this disease. Until the etiopathogenesis of PSC is further defined, effective therapy is unlikely to be found. Thus, liver transplantation will continue to be an important therapeutic intervention for the management of patients with end-stage PSC.

Primary sclerosing cholangitis: Refinement and validation of survival models

The natural history of primary sclerosing cholangitis was studied in 426 patients from five medical centers. The median follow-up time was 3.0 years (range, 0.01-16.6 years); 100 patients had died by the time of last follow-up. Survival analysis (Cox proportional-hazards regression) was used to identify the variables most useful in predicting survival of patients with primary sclerosing cholangitis. Serum bilirubin concentration, histological stage on liver biopsy, age, and the presence of splenomegaly were independent predictors of a high risk of dying. A mathematical model to predict survival of patients with primary sclerosing cholangitis (based on referral values of those predictors) was statistically validated using two methods. Confidence intervals for predicting patient-specific survival probabilities are also presented. This model to predict survival could be used to stratify participants in therapeutic trials, counsel patients and their families, decide on candidacy for and timing of liver transplantation, and provide mathematical controls for evaluating the efficacy of therapies for primary sclerosing cholangitis, including transplantation.

REVIEW: Nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a reasonably well‐defined clinicopathological entity; it has been reported more commonly in women than in men or children of both sexes and it appears to be most closely associated with obesity, diabetes mellitus and related abnormalities, such as hyperlipidaemia and hyperglycaemia. However, the association with female gender, obesity and diabetes may not be as close as suggested by the literature and an underlying condition cannot be discerned in all cases. The natural history of the disease is poorly understood; the associated biopsy features span a wide spectrum, reaching from uncomplicated, clinically non‐progressive fatty liver (not NASH in a strict sense) to a slowly progressive fatty liver with inflammation and fibrosis, to steatohepatitis with submassive hepatic necrosis, which has a subfulminant course and is often fatal. Non‐progressive fatty liver appears to be very common but is of little clinical importance. The slowly progressive form of the disease represents NASH as encountered by most clinicians and pathologists. It is a common liver disease in current practice; patients may present with cirrhosis and even HCC arising from steatohepatitic cirrhosis. Subfulminant NASH has become exceedingly rare because many clinicians are now aware of the hazards of sudden weight loss, particularly in morbidly obese patients. Treatment options for NASH are still limited. The promotion of gradual weight loss in obese patients is the most widely recommended therapy but, unfortunately, this is very difficult to achieve. Avoidance of precipitous weight loss and careful control of diabetes mellitus are important and undisputed parts of patient management. Administration of UDCA as a treatment of NASH is still under study; it may be effective in some patients. The treatment of established steatohepatitic cirrhosis does not differ substantially from that of other types of cirrhosis and includes orthotopic liver transplantation.

A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis

Primary biliary cirrhosis is a progressive disease of the liver characterized by the immunologic destruction of bile ducts; effective therapy is lacking. We therefore evaluated the safety and efficacy of low-dose cyclosporine in 29 patients with primary biliary cirrhosis without evidence of damage to the lobular architecture (precirrhotic disease) or portal hypertension. The patients were randomly assigned to receive either cyclosporine (4 mg per kilogram of body weight per day) or placebo. After one year 17 of the 19 patients assigned to cyclosporine had improvement or stability in their degree of fatigue, and 18 in their degree of pruritus. In contrast, among the 10 patients assigned to placebo, fatigue increased in 4 (P less than 0.06) and pruritus worsened in 6 (P less than 0.001). Those assigned to cyclosporine also had significant decreases in serum levels of bilirubin, alanine aminotransferase, alkaline phosphatase, gamma globulin, and the titer of antimitochondrial antibodies. For the 20 patients who have completed two years in the study, liver biopsies (coded specimens) showed evidence of histologic progression in only 1 of 13 patients in the cyclosporine group, as compared with 5 of 7 in the placebo group (P less than 0.003). No patient has permanently discontinued cyclosporine because of side effects; however, signs of nephrotoxicity developed in 12 of 19, and 9 of 19 had increased blood pressure. We conclude that in patients with precirrhotic primary biliary cirrhosis, immunosuppressive therapy with cyclosporine is promising and deserves further evaluation.

Comparison of the Clinicopathologic Features of Primary Sclerosing Chol-angitis and Primary Biliary Cirrhosis

Primary sclerosing cholangitis and primary biliary cirrhosis are chronic cholestatic syndromes that may be difficult to differentiate clinically. Destructive cholangitis occurs in both diseases and leads to similar clinical and biochemical abnormalities. Therefore, we compared the clinical, biochemical, immunologic, radiologic, and hepatic histologic features of these syndromes in two large groups of patients prospectively selected by predefined criteria. Primary biliary cirrhosis (n = 258) occurred predominantly in middle-aged women who were usually symptomatic with fatigue and pruritus, commonly had keratoconjunctivitis sicca, and often were hyperpigmented. Tests for antimitochondrial antibodies were always positive, usually in very high titer. Although the extrahepatic bile ducts were normal radiographically, smooth tapering and narrowing of the intrahepatic bile ducts was occasionally noted. Hepatic histology was diagnostic when a florid duct lesion was present. In contrast, primary sclerosing cholangitis (n = 60) occurred primarily in young men who were usually symptomatic with fatigue and pruritus and frequently had chronic ulcerative colitis. Tests for antimitochondrial antibodies were nearly always negative and cholangiography demonstrated abnormalities of the extrahepatic and intrahepatic bile ducts in all cases. Although hepatic histology was often compatible with the diagnosis, it was usually not diagnostic, and considerable overlap existed with the abnormalities seen in primary biliary cirrhosis. Likewise, biochemical tests of copper metabolism were similar in both syndromes. These results call attention to the differences and similarities in the clinicopathologic features of these two cholestatic syndromes and provide a basis for a rational diagnostic strategy.