Staffan Wahlin

Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases.

Aim To assess the prevalence of concurrent extrahepatic autoimmune diseases in patients with autoimmune hepatitis (AIH)/primary biliary cirrhosis (PBC) overlap syndrome and applicability of the ‘mosaic of autoimmunity’ in these patients. Methods The medical data of 71 AIH/PBC overlap patients were evaluated for associated autoimmune diseases. Results In the study population, 31 (43.6%) patients had extrahepatic autoimmune diseases, including autoimmune thyroid diseases (13 patients, 18.3%), Sjögren syndrome (six patients, 8.4%), celiac disease (three patients, 4.2%), psoriasis (three patients, 4.2%), rheumatoid arthritis (three patients, 4.2%), vitiligo (two patients, 2.8%), and systemic lupus erythematosus (two patients, 2.8%). Autoimmune hemolytic anemia, antiphospholipid syndrome, multiple sclerosis, membranous glomerulonephritis, sarcoidosis, systemic sclerosis, and temporal arteritis were identified in one patient each (1.4%). A total of 181 autoimmune disease diagnoses were found in our patients. Among them, 40 patients (56.4%) had two, 23 (32.3%) had three, and eight (11.3%) had four diagnosed autoimmune diseases. Conclusion A large number of autoimmune diseases were associated with AIH/PBC overlap patients. Therefore, extended screening for existing autoimmune diseases during the routine assessment of these patients is recommended. Our study suggests that the concept of ‘mosaic of autoimmunity’ is a valid clinical entity that is applicable to patients with AIH/PBC overlap syndrome.

Combined liver and kidney transplantation in acute intermittent porphyria

We report two patients with acute intermittent porphyria (AIP) who were successfully treated with combined liver and kidney transplantation. Both had a very poor quality of life as a result of years of frequent acute porphyria symptoms, chronic peripheral neuropathy and renal failure requiring dialysis. After transplantation, clinical and biochemical signs of porphyria disappeared. The excretion pattern of porphyrin precursors normalized within the first day and plasma porphyrins returned to normal within a week. These and other recent cases have clarified previous concerns and have helped to formulate the indications for and the timing of transplantation in AIP.

Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics.

Abstract.  Wahlin S, Floderus Y, Stål P, Harper P (Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden). Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics. J Intern Med 2010; 269: 278–288.

Autoimmune liver disease in patients with systemic lupus erythematosus: A retrospective analysis of 147 cases

Abstract Objective. We aimed to investigate the characteristics of autoimmune liver disease (AILD) developed in patients with systemic lupus erythematosus (SLE), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and the AIH/PBC overlap syndrome. We also evaluated the accuracy of diagnostic criteria and scoring systems for AILD in SLE. Methods. A retrospective analysis of patients attending the rheumatology and gastroenterology clinics in Ankara, Turkey, between 1999 and 2010. SLE patients with elevated liver enzymes were investigated for liver diseases. Results. A total of 147 SLE patients were identified and 36 of them had liver enzyme abnormalities. AILD was diagnosed in 4.7% of all SLE patients, in 19.4% of those with elevated liver enzymes. Of patients with liver enzyme abnormalities, 72.3% fulfilled the criteria for AIH proposed by the International Autoimmune Hepatitis Group (IAIHG), whereas 66.7% had AIH by using the simplified criteria. Yet, only 13.8% of these patients had liver biopsy findings consistent with AIH. Patients with AILD were treated with conventional therapy including ursodeoxycholic acid, prednisolone, azathioprine or combinations of these. Treatment failure and subsequent advanced liver disease developed in one patient. Conclusions. AILD may occur during the course of SLE. Due to biochemical similarities between AIH and SLE, AIH could be considered very probable by using both IAIHG scoring system and simplified criteria. For definitive diagnosis of AIH, liver biopsy should be performed in all SLE patients with chronic enzyme abnormalities. The response to therapy is favorable in these patients, and early diagnosis is important for preventing advanced liver disease.

Factors Associated With Response to Therapy and Outcome of Patients With Primary Biliary Cirrhosis With Features of Autoimmune Hepatitis

BACKGROUND & AIMS For patients with primary biliary cirrhosis (PBC) with features of autoimmune hepatitis (AIH), treatment with ursodeoxycholic acid (UDCA) alone or in combination with immunosuppression is controversial. Little is known about the factors associated with initial response to therapy or outcome. We performed a retrospective analysis of treatment strategies and factors associated with outcomes of patients with PBC-AIH. METHODS We analyzed data from 88 patients who were diagnosed with PBC-AIH according to Paris criteria, from 7 centers in 5 countries. First-line therapies included UDCA alone (n = 30) or a combination of UDCA and immunosuppression (n = 58). RESULTS Of patients who received UDCA alone as the first-line therapy, 37% did not respond to treatment. Severe interface hepatitis was independently associated with lack of response to treatment (P = .024; odds ratio, 0.05; 95% confidence interval, 0.004-0.68). The combination of UDCA and immunosuppression was effective in 73% of patients who had not been previously treated or had not responded to UDCA. The presence of advanced fibrosis was associated with lack of response to the combination of UDCA and immunosuppression (P = .003; odds ratio, 0.13; 95% confidence interval, 0.03-0.48). Second-line immunosuppressive agents (cyclosporine, tacrolimus, and mycophenolate mofetil) led to biochemical remission in 54% of patients who did not respond to initial immunosuppression. Liver transplants were given to 4 patients with PBC-AIH. Five patients died during follow-up (3 from liver-related causes). CONCLUSIONS In a retrospective study of a large cohort of patients with PBC-AIH, UDCA alone did not produce a biochemical response in most patients with severe interface hepatitis; these patients require additional therapy with immunosuppression. Second-line immunosuppressive agents are effective in controlling disease activity in patients who do not respond to conventional immunosuppression.

Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria.

Erythropoietic protoporphyria is an inherited condition characterized by pronounced solar photosensitivity and in a minority of patients severe liver disease that necessitates liver transplantation for survival. Phototoxic injury to abdominal organs and skin has been reported in several cases of liver transplantation surgery, including a few transplants in which protective light filters were used. This study discusses the optimal characteristics of light filters used during liver transplantation surgery. An experimental model is used to evaluate the relative protection of different filters, and the results are compared with theoretical calculations regarding the risk for phototoxic injury from light sources in health‐care procedures. Whether protective measures are warranted in other illuminated procedures besides liver transplantation has been discussed often but never studied. This study elucidates the risk for phototoxic injury in endoscopy, laparoscopy, and non–liver transplant surgery. A theoretical model and epidemiological data are considered. Our findings indicate that endoscopy, laparoscopy, and surgical procedures other than liver transplantation are safe in the noncholestatic protoporphyria patient and that general recommendations for using filters in these situations are not warranted. Among the tested filters, a flexible yellow filter omitting wavelengths below 470 nm is recommended for liver transplant surgery. This filter has been readily accepted by surgeons and offers a good balance between protection and altered visual color perception. The experimental model, using hemolysis of protoporphyrin‐loaded erythrocytes as a measure of phototoxicity, has substantiated theoretical findings on relative filter protection. Liver Transpl 14:1340–1346, 2008.

Liver Transplantation for Erythropoietic Protoporphyria in Europe

Liver transplantation is an established lifesaving treatment for patients with severe protoporphyric liver disease, but disease recurrence in the graft occurs for the majority of recipients. Severe burn injuries may occur when protective light filters are not used with surgical luminaires. Motor neuropathy with an unclear pathogenesis is a frequent complication. We retrospectively studied 35 transplants performed for protoporphyric liver disease in 31 European patients between 1983 and 2008. Most of the patients were male (61.3%), and the mean age at the time of primary transplantation was 39 years (range = 9‐60 years). The overall patient survival rates were 77% at 1 year and 66% at 5 and 10 years. The overall rate of disease recurrence in the graft was 69%. Forty‐three percent of the patients experienced recurrence within a year, but this was often a transient finding that was associated with other graft complications. Phototoxic injuries due to surgical luminaires were seen in 25.0% of the patients who were not protected by filters, but these injuries were not seen in the 9 patients who were protected by filters. Significant motor neuropathies requiring prolonged ventilation complicated the postoperative course for 5 of the 31 patients (16.1%). Hematopoietic stem cell transplantation was performed for 3 patients to prevent graft loss due to disease recurrence. Prognostic markers are needed to identify patients prone to severe protoporphyric liver disease so that curative stem cell transplantation can be offered to select patients instead of liver transplantation. Liver Transpl 17:1021–1026, 2011.

Antibodies to soluble liver antigen in patients with various liver diseases: A multicentre study

Antibodies to soluble liver antigen (anti‐SLA) are specific serological markers of autoimmune hepatitis (AIH). The clinical significance and frequency of anti‐SLA have never been reported among AIH patients from Italy and Turkey.

Pregnancy in women with primary biliary cirrhosis

BACKGROUND & AIMS Primary biliary cirrhosis (PBC) may present in all decades of life, also in childbearing age. Data on maternal and fetal outcome is limited. We aimed to investigate the impact of pregnancy and childbirth on the disease course and possible effects of PBC on fetal outcome. METHODS Retrospective study of local cases and a compact review of published reports between 1950 and 2014. RESULTS Our cases along with literature review provided 98 pregnancies in 72 PBC patients. PBC was diagnosed during pregnancy in 26 (36%) patients and 46 (64%) had the diagnosis before conception. Twenty-four (30%) of the pregnancies were associated with biochemical flares and 55 (70%) with clinical improvement or stabilization. De novo onset or worsening of pruritus was seen in 49% (45/92). No maternal deaths were reported. Post-partum disease activation was observed in 60% (53/88). One patient was referred for liver transplantation after delivery. A miscarriage rate of 24% and three stillbirths were reported. Most patients were treated with ursodeoxycholic acid (UDCA) during breastfeeding and 12 patients also received UDCA during the first trimester without any identified side effects. CONCLUSION Most women with PBC maintain a stable disease during pregnancy, but post-partum biochemical flares are common. Symptomatic pruritus may be challenging in pregnant PBC patients. UDCA appears to be safe during pregnancy and breastfeeding. A successful pregnancy outcome is a realistic expectation for women with PBC.

Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis

BACKGROUND & AIMS: Predniso(lo)ne, alone or in combination with azathioprine, is the standard‐of‐care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second‐line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second‐line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second‐line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver‐related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log‐rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long‐term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.