Cholestatic liver diseases in adults

Cholestatic liver diseases are a diverse group of disorders that are recognized by either increases in laboratory studies or the appearance of jaundice, fatigue, pruritus, and/or complications of cirrhosis. The etiologies for most forms of these diseases are unknown. In this paper, diagnostic and therapeutic strategies are reviewed for select forms of cholestatic disorders and for the management of shared complications of cholestatic illness.     

Cholestatic liver diseases and health-related quality of life

OBJECTIVE: Symptoms associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) negatively affect health-related quality of life (HRQL). The aim of this study was to measure HRQL in patients with chronic cholestatic liver diseases and to determine factors associated with more severe impairment. METHODS: We conducted a cross-sectional study in which we documented patients' demographic and clinical characteristics, and measured their HRQL using the Short Form-36 and Chronic Liver Disease Questionnaire. We assessed the association of HRQL impairment with disease severity (Child's-Pugh class and Mayo PBC Risk Score) and compared patients' HRQL with those of a healthy population, and patients with congestive heart failure, chronic obstructive pulmonary disease, and diabetes. RESULTS: One hundred and four patients with PBC and PSC participated, of whom 73% were women, with an average age of 55+/-12 yr. Of these patients, 61% had cirrhosis (37% Child's A, 23% Child's B, and 2% Child's C). Patients with cholestatic liver disease showed more HRQL impairment than the healthy population and were similar to patients with other chronic conditions. Additionally, patients who experienced severe itching showed profound HRQL impairment. In patients with PBC, Physical Component Summary (PCS) scores of the SF-36 and Chronic Liver Disease Questionnaire (CLDQ) scores fell from noncirrhotic to Child's A to Child's B/C and with worsening Mayo PBC Risk Scores. No other clinicodemographic data were associated with patients' well-being. CONCLUSIONS: Patients with cholestatic liver disease (PBC and PSC) showed substantial impairment of HRQL, which is further affected by worsening disease severity. Disease-specific measures were better able to discriminate patients with varying severities.     

Recurrence of autoimmune liver diseases after liver transplantation

Liver transplantation(LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis(AIH) and primary biliary cirrhosis(PBC), but not for primary sclerosing cholangitis(PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease(AIH, PBC, PSC) following LT.     

Cholestatic liver diseases: slow progress in understanding and treating slowly progressive disorders

BACKGROUND: Cholestatic liver diseases are characterized by failure of normal amounts of physiological bile to reach the gastrointestinal tract. Any interference with normal bile flow from the canalicular membrane of the hepatocyte to the distal common bile duct may result in cholestasis. METHODS: Literature review. RESULTS: In primary biliary cirrhosis (PBC), the small intrahepatic bile ducts are destructed, resulting in obstruction of intrahepatic bile flow, whereas extrahepatic and/or intrahepatic biliary strictures block the passage of bile towards the intestine in primary sclerosing cholangitis (PSC). In contrast, the biliary tree is morphologically unaffected in less common cholestatic liver diseases as benign recurrent intrahepatic cholestasis (BRIC) and progressive familiar intrahepatic cholestasis (PFIC1-4). Genetic defects in hepatic canalicular transport mechanisms and bile salt synthesis deficiencies seem to underlie these types of cholestatic disorders. CONCLUSION: Recent advances in understanding and treatment of cholestatic liver diseases may help in better diagnosing and treating the various conditions characterized by cholestasis.     

Indications for liver transplantation in chronic liver diseases

Surgical resection of the diseased liver together with the implantation of a new donor organ allows patients with chronic liver failure to survive longer as well as to achieve a better quality of life. In life-threatening acute and chronic hepatic failure liver transplantation represents the only causal and long-term therapeutic option. This is also true for several genetically defined liver diseases. Five-year survival approaches 70 % in most cases. Three of four patients regain a nearly normal life with complete reintegration into their professional work. Drawbacks of this therapeutic option relate to a life-long dependence on drugs and medical services as well as to the risks associated with the surgical procedure and the side-effects of a continuous drug-induced immunosuppression. Mortality and morbidity are considerably increased during the first three months after operation. These limitations and the dramatically low availability of donor organs necessitate the application of all conservative measures before a transplantation procedure should be performed. However, the surgical option should be evaluated early enough to allow for a good chance of success. Profound knowledge of prognosis and medical treatment of each individual liver disease is a prerequisite for correct indication and timing of liver transplantation.     

Cholestatic hepatitis due to hepatitis C virus after a living donor liver transplantation

Recurrence of hepatitis C virus after liver transplantation is common and cholestatic hepatitis occurs in approximately 10% of the patients and leads to accelerated graft failure and death. A 47-year-old man underwent living donor liver transplantation for hepatitis C-related liver cirrhosis. Preemptive antiviral therapy was started using interferon-alpha2b (6 MU x 3 per week) and ribavirin (600 mg per day) two months after living donor liver transplantation. The response to the combined therapy was not satisfactory. He developed liver failure and expired 11 months after the transplantation. The present results indicate that a rapid development of graft failure can occur in spite of preemptive antiviral therapy after living donor liver transplantation.     

Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.     

Clinical analysis of liver transplantation in autoimmune liver diseases

Background: Autoimmune liver diseases(ALDs) consist of autoimmune hepatitis(AIH), primary biliary cirrhosis(PBC), primary sclerosing cholangitis(PSC), Ig G4-associated cholangitis and overlap syndromes.Patients with these diseases may gradually progress to end-stage liver diseases and need liver transplantation. The present study aimed to explore the prognosis of patients with ALDs after liver transplantation.Methods: The clinical data of 80 patients with ALD(24 cases of AIH, 35 of PBC, 15 of PSC and 6 of AIHPBC overlap syndromes) who underwent liver transplantation in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2004 to September 2016 were collected retrospectively. The causes of death were analyzed and the postoperative cumulative survival rate was estimated by the Kaplan–Meier method. Recurrence and other complications were also analyzed.Results: Of the 80 patients, 18 were males and 62 were females. The average age was 50.5 years and the average Model for End-stage Liver Disease(MELD) score was 14.1. After a median follow-up of 19.8 months, 8 patients died. The 1-, 3-and 5-year cumulative survival rates were all 89.0%. Three cases of recurrent ALDs were diagnosed(3.8%) but they were not totally consistent with primary diseases. Biliary tract complication occurred in 10 patients(12.5%). The new onset of tumor was observed in 1 patient(1.3%). De novo HBV/CMV/EBV infection was found in 3, 8 and 3 patients, respectively.Conclusion: Liver transplantation is an effective and safe treatment for end-stage ALD.     

Liver transplantation for metabolic liver diseases

Liver transplantation has become an accepted treatment for several metabolic liver diseases. With advances in organ transplantation and immunosuppressive strategies, survival rates following liver transplantation are generally excellent. When the primary metabolic defect is hepatic in origin, liver transplantation not only replaces the dysfunctional organ but also cures the underlying metabolic defect. For conditions in which the primary metabolic defect is extrahepatic, liver transplantation is usually performed for hepatic complications, although disease recurrence may occur. This article reviews common metabolic liver diseases treated with liver transplantation in the adult population.     

Liver transplantation in metabolic liver diseases

Abstract   Two types of metabolic disorders are treated with transplantation: those associated with severe liver damage, like alpha-1 antitrypsin deficiency, progressive familial cholestatic syndromes, tyrosinaemia, glycogen storage diseases, or cystic fibrosis; and those in which the liver is structurally normal, but is genetically unable to produce an essential protein, usually an enzyme, with consequent lethal systemic disease, like Crigler-Najjar syndrome, familial hypercholesterolaemia, propionic acidaemia, or urea cycle defects. The first group of diseases, among which the most common is alpha-1 antitrypsin deficiency, are treated by substitution of the whole liver with the donor liver, while the second group can be treated by auxiliary transplantation, to provide sufficient production of the deficient protein by the donor liver segment, while the native liver provides a safety net should the transplant fail and remains available for possible future gene therapy. In recent years, attempts have been made to treat these conditions by isolated human hepatocyte transplantation, with temporary success.     

Cholestatic liver diseases from child to adult: the diversity of MDR3 disease

The phospholipidfloppase MDR3 (gene symbol: ABCB4) is expressed in the canalicular membrane of hepatocytes and mediates the biliary excretion of phosphatidylcholine, which is required for the formation of mixed micelles in bile. Several mutations of ABCB4 have been identified, which cause cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 3 (PFIC-3), intrahepatic cholestasis of pregnancy (ICP) and the low phospholipid associated cholelithiasis syndrome (LPAC). Here, we report on four new (S1076N; L 23Hfs16X; c.286 + 1G > A; Q 1181E) and one known (S27G) MDR3 mutations in eight patients of three families. The patients presented with a wide spectrum of liver diseases. The clinical presentation and decisive laboratory findings or the association to a trend-setting family history led to the identification of the genetic background in these patients. Even the same mutation may be associated with varying disease progression.     

Recurrence of diseases following orthotopic liver transplantation

Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disese recurrence.