Elevated Serum Alkaline Phosphatase Levels Research Articles

Morin protects acute liver damage by carbon tetrachloride (CCl4) in rat

The purpose of this study was to investigate possible beneficial effects of morin on CCl(4)-induced acute hepatotoxicity in rats. Rats received a single dose of CCl(4) (150 microL/100 g 1:1 in corn oil). Morin treatment (20 mg/kg) was given at 48, 24, and 2 h before CCl(4) administration. CCl(4) challenge elevated serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) levels, but these effects were prevented by the pretreatment of rats with morin. To identify the mechanism of protective activity of morin in CCl(4)-induced hepatotoxicity in rats, we investigated expressions of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and inducible nitric oxide (iNOS). The expressions of TNF-alpha, IL-1beta, IL-6, and iNOS were increased by CCl(4) treatment and increased expressions of those were decreased by morin. These findings suggest that morin prevents acute liver damage by inhibiting the production of TNF-alpha, IL-1beta, IL-6, and iNOS.

Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer

Using laser-captured microdissection and a real-time RT–PCR assay, we quantitatively evaluated mRNA levels of the following biomarkers in paraffin-embedded gastric cancer (GC) specimens obtained by surgical resection or biopsy: excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), methylenetetrahydrofolate reductase (MTHFR), epidermal growth factor receptor (EGFR), and five other biomarkers related to anticancer drug sensitivity. The study group comprised 140 patients who received first-line chemotherapy for advanced GC. All cancer specimens were obtained before chemotherapy. In patients who received first-line S-1 monotherapy (69 patients), low MTHFR expression correlated with a higher response rate (low: 44.9% vs high: 6.3%; P=0.006). In patients given first-line cisplatin-based regimens (combined with S-1 or irinotecan) (43 patients), low ERCC1 correlated with a higher response rate (low: 55.6% vs high: 18.8%; P=0.008). Multivariate survival analysis of all patients demonstrated that high ERCC1 (hazard ratio (HR): 2.38 (95% CI: 1.55–3.67)), high DPD (HR: 2.04 (1.37–3.02)), low EGFR (HR: 0.34 (0.20–0.56)), and an elevated serum alkaline phosphatase level (HR: 1.00 (1.001–1.002)) were significant predictors of poor survival. Our results suggest that these biomarkers are useful predictors of clinical outcomes in patients with advanced GC.

A case of severe hypophosphatemia related to adefovir dipivoxil treatment in a patient with liver cirrhosis related to hepatitis B virus

Adefovir dipivoxyl (ADV) effectively suppresses hepatitis B virus (HBV) replication but exhibits nephrotoxicity with severe hypophosphatemia when administered at a high dosage. This is the first report of severe hypophosphatemic osteomalacia induced by ADV at 10 mg/day. A 42-year-old man with HBV-related chronic liver disease presented with generalized bone pain, especially in the left ankle. He had been taking ADV for more than 1.5 years following a clinical breakthrough due to lamivudine-resistant HBV. Aggravating severe hypophosphatemia and elevated serum alkaline phosphatase levels with high bone fraction had been noted after 6 months of ADV therapy. Bone densitometry, simple bone X-rays, and a whole-body bone scan demonstrated osteoporosis and multiple areas with hot uptake, especially in the left ankle. All the image findings and symptoms improved after correcting the hypophosphatemia.

Bisphosphonates in Paget’s Disease of Bone

Paget’s disease of bone is a chronic focal bone remodeling disorder with distinctive geographic occurnece. In the US, 1.8% of people over 60 years of age are affected. At present, 70% of patients are asymptomatic with the most common presenting symptoms being bone pain, osteoarthritis, and bone deformity. Paget’s disease is usually easily diagnosed by an elevated serum alkaline phosphatase level, a bone scan and skeletal radiographs of area that show increased activity on the bone scan. There is no cure for this disorder; however, a class of drugs, the bisphosphoates, can control the elevated bone remodeling rates, improve osteolytic skeletal lesions and attendant bone pain. The most effective bisphosphonates are the nitrogen-containing compounds, which can be administered orally or intravednously.

Detecting extrathoracic metastases in patients with non-small cell lung cancer: Is routine scanning necessary?

There is controversy over whether to scan extrathoracic sites for metastases in patients with non-small cell lung cancer (NSCLC). We tested the efficiency of clinical factors to determine whether metastasis has occurred, and whether routine scanning for NSCLC is required. Nine hundred and forty five patients scanned for extrathoracic metasates were included. Clinical factors indicating metastasis were determined using multivariate analysis. Of the 945 cases, 377 (39.9%) had metastasis. Bone metastases were determined by focal skeleton pains, elevated serum alkaline phosphatase levels, adenocarcinoma, KPS</=70, sensitivity of 90.6, specificity of 12.7, PPV of 16.3, NPV of 87.8, and silent metastases rate (SMR) of 9.4%. Brain metastases were determined by neurological symptoms, adenocarcinoma, hematocrite <40 for men and <35 for women, KPS</=70, sensitivity of 89.9, specificity of 7.9, PPV of 9.2, NPV of 88.3, and SMR of 10.1%. Abdominal metastases were determined by abdominal pain/tension, hepatomegaly, elevated GGT levels, serum LDH levels >500 IU, a N2 or N3 case, KPS</=70, sensitivity of 95.9, specificity of 7.1, PPV of 13.3, NPV of 92.1 and SMR of 4.1%. Of the 224 patients with stage I and II disease, 73 had metastasis with a rate of 10.9% silent metastasis. We concluded that routine scanning of NSCLC for staging is necessary.

OCCURRENCE OF HEPATOCELLULAR CARCINOMA IN AN ADULT MALE NILE LECHWE (KOBUS MEGACEROS)

A 14-yr-old male Nile lechwe (Kobus megaceros) from the Jackson Zoo (Mississippi, USA) had chronic weight loss that was associated with elevated serum alkaline phosphatase levels. Approximately 4 yr after the first clinical signs of weight loss, the animal fractured its left rear femur and was subsequently euthanized; on the same day necropsy was performed. The liver was grossly enlarged and contained a smooth-surfaced nodular mass that occupied the majority of the right lobe of the liver. The mass had a liver-like appearance exhibiting a tan-red coloration but having a soft consistency. A single, approximately 0.6 cm, round, slightly elevated discrete red nodule was present in the left anterior lung. Microscopically, the hepatic mass and pulmonary nodule diffusely consisted of irregular cords of cells exhibiting hepatoid features, but containing no evidence of normal portal bile duct or portal triad development. To our knowledge, this is the first report in the scientific literature of a naturally occurring case of hepatocellular carcinoma in a Nile lechwe or in any antelope species.

Pure White Cell Aplasia: Report of the First Case Associated with Primary Biliary Cirrhosis

Pure white cell aplasia (PWCA) is a rare hematologic disorder characterized by agranulocytosis, a lack of virtually all neutrophil-lineage cells (from neutrophils to myeloblasts) in the bone marrow, and normal erythropoiesis and megakaryocy-topoiesis. We report the first case of PWCA that developed in a patient with primary biliary cirrhosis (PBC). An 83-year-old woman, who had had an elevated serum alkaline phosphatase level and shown positivity for serum antimitochondrial antibodies for 10 years, was referred to us because of a perianal abscess. She had severe neutropenia, and her bone marrow showed typical findings of PWCA. Although methylprednisolone pulse therapy induced complete neutrophil recovery, this effect was transient. She died of infection, and the autopsy confirmed the diagnosis of PBC. In vitro investigations showed that factors inhibitory to normal CD34 cell-derived granulopoiesis were present in the patient's serum.

Transitional Cell Carcinoma of the Ureter: Prognostic Factors Influencing Progression and Survival

ObjectivesWe retrospectively evaluated prognostic factors for progression-free and disease-specific survival in a large cohort of patients with transitional cell carcinoma (TCC) of the ureter. MethodsA single-centre series of 145 consecutive patients treated with partial resection of the ureter or nephroureterectomy between 1975 and 2004 was evaluated. Median follow-up was 96 mo. Routine preoperative laboratory parameters as well as clinical and tumour-specific data were assessed. Univariate and multivariate statistical analyses were performed. ResultsFive-year disease-specific survival ranged from 96.1% for stages pTa to 28.6% for pT4. Grade1 tumours were associated with 5-yr disease-specific survival rates of 100% compared with 84% for G2, and 51.9% for G3 tumours, respectively. Univariate analyses identified pT stage and grade, tumour diameter, cM and pN categories, weight loss, the presence of synchronous tumour in the renal pelvis as well as elevated levels for humoral factors such as serum alkaline phosphatase (AP), white blood cell (WBC) count, platelet count, γ-glutamyl transferase, creatinin, and blood urea nitrogen as prognostic factors. In multivariate analyses, tumour grade and WBC counts were predictive for low progression-free survival rates, whilst simultaneous tumour in the renal pelvis, high AP levels, and WBC counts were correlated with worse disease-specific survival. ConclusionsOur retrospective analysis provides clinical factors to identify patients with TCC of the ureter at high risk for progression and death of disease. Interestingly, humoral factors such as elevated serum AP levels and high WBC counts were demonstrated to be of paramount prognostic significance besides tumour stage, grade and multifocality.

Ossäre Metastase eines Prostatakarzinoms simuliert ein Paget-Sarkom

A 74-year-old man presented with bone pain of the right hip, night sweat and weight loss for 18 months. The diagnosis of Paget's disease was confirmed four months before admission, but pain and elevated serum alkaline phosphatase levels remained despite treatment with i.v. bisphosphonates. The physical examination showed no specific abnormalities. Laboratory findings were elevated levels of serum alkaline phosphatase (AP), CA 19-9 and CEA. Radiological and tomographic images showed an aggressive periostal reaction consistent with Paget's sarcoma. The bone biopsy revealed the presence of prostatic cancer which was confirmed in a subsequent prostate biopsy. Because of the multiple bone and lung metastases the disease proved to be incurable and the patient received palliative therapy with flutamide. He died 12 months later. In patients with Paget's disease lacking of response to bisphosphonate administration (permanently increased AP and sustained pain) radiological and clinical re-assessment of the diagnosis is indicated and may sometimes also include bone biopsy.

Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin

Increased expression of several osteoblastic proteases and MEPE (a bone matrix protein) occurs in X-linked hypophosphatemic rickets (hyp). This is associated with an increased release of a protease-resistant MEPE peptide (ASARM peptide), a potent inhibitor of mineralization. Cathepsin B cleaves MEPE releasing ASARM peptide and hyp osteoblast/osteocyte cells hypersecrete cathepsin D, an activator of cathepsin B. Our aims were to determine whether cathepsin inhibitors correct the mineralization defect in vivo and whether hyp-bone ASARM peptide levels are reduced after protease treatment. Normal littermates and hyp mice ( n = 6) were injected intraperitoneally once a day for 4 weeks with pepstatin, CAO74 or vehicle. Animals were then sacrificed and bones plus serum removed for comprehensive analysis. All hyp mice groups (treated and untreated) remained hypophosphatemic with serum 1,25 vitamin D3 inappropriately normal. Serum PTH was significantly elevated in all hyp mice groups relative to normal mice ( P = 0.0017). Untreated hyp mice had six-fold elevated levels of serum alkaline-phosphatase and two-fold elevated levels of ASARM peptides relative to normal mice ( P < 0.001). In contrast, serum alkaline phosphatase and serum ASARM peptides were significantly reduced (normalized) in hyp mice treated with CA074 or pepstatin. Serum FGF23 levels remained high in all hyp animal groups ( P < 0.0001). Hyp mice treated with protease inhibitors showed dramatic reductions in unmineralized osteoid (femurs) compared to control hyp mice (Goldner staining). Also, hyp animals treated with protease inhibitors showed marked and significant improvements in growth plate width (42%), osteoid thickness (40%) and cortical area (40%) ( P < 0.002). The mineralization apposition rate, bone formation rate and mineralization surface were normalized by protease-treatment. High-resolution pQCT mineral histomorphometry measurements and uCT also confirmed a marked mineralization improvement. Finally, the growth plate and cortical bone of hyp femurs contained a massive accumulation of osteoblast-derived ASARM peptide(s) that was reduced in hyp animals treated with CA074 or pepstatin. This study confirms in vivo administration of cathepsin inhibitors improves bone mineralization in hyp mice. This may be due to a protease inhibitor mediated decrease in proteolytic degradation of the extracellular matrix and a reduced release of ASARM peptides (potent mineralization inhibitors).

Acute laryngotracheobronchitis and associated transient hyperphosphatasemia: A new case of transient hyperphosphatasemia in early childhood

We report the case of a 20-month old boy with markedly elevated serum alkaline phosphatase (ALP) levels, documented during an episode of acute laryngotracheobronchitis. Biochemical investigations and imaging studies revealed no evidence of bone or liver disease. Transient hyperphosphatasemia (TH) was confirmed when serum ALP levels normalized within 2 months. Several theories were suggested for TH pathophysiology, viral infections among them; the exact causes, however, remain unclear. It is important to recognize TH and avoid misdiagnosis and unnecessary investigations.

Marked Bone Marrow Necrosis Proceeding Acute Monoblasic Leukemia.

Bone marrow necrosis (BMN) is a rare antemortem diagnosis with obscure ethiology. This entity is diagnosed mostly at postmortem examination, but it is also seen during the course of different diseases, mostly malignant.It is characterized morphologically by destruction of hemopoeitic tissue, including the stroma, with preservation of the bone.Conditions associated with BMN include infections, acute and chronic leukemia, Hodgkin's and non-Hodgkin's lymphoma, primary thrombocythemia, and metastatic carcinoma. It has also been reported in the presence of antiphospholipid antibodies, previous irradiation, antineoplastic chemotherapy, and during treatment with all-transretinoic acid, fludarabine, interferon alpha, and granulocyte-colony-stimulating factor (G-CSF). Other non-neoplastic conditions include disseminated intravascular coagulation (DIC), sickle cell disease, anorexia nervosa and idiopathic conditions.The prognosis of patients with bone marrow necrosis secondary to neoplastic diasease is extremely poor. Report of complete recovery of four children with ALL who presented with bone marrow necrosis is documented. The relative frequency of BMN varies among different reports, ranging between 0.37%–6.5% of bone marrows. Elevated serum lactate dehydrogenase and alkaline phosphatase levels are known associated laboratory features and were also seen in our patient. We described a 23 years old woman with bone marrow necrosis who developped acute monoblastic leukemia.She was admitted in May, 2004 with generalized bone pain and normocytic anemia. At that time her bone marrow examination showed bone marrow necrosis. She received mostly supportive care during this phase of her presentation because of the possibility of myelodisplastic syndrome. She did not have much pain and discomfort during this phase of her disease. After 8 months she was readmited with severe generalized bone pain and mild pancytopenia. with possible infection or exacerbation of her disease. Bone marrow aspiration and biopsy were repeated. Cytomorphology, enzyme cytochemistry and results of flow cytometric analysis were compatible with Acute Monoblastic Leukemia with mimimal differentiation 80% nonerythroid bone marrow cells are monocyte lineage(AML/M5a), monoblast granules were nonspecific esterase positive, myeloperoxidase negative and more mature monocyte lineage cells had weakly myeloperoxidase positive naphtol b-esterse was positive, naphtol a-estterase was negative and flow cytometic antibody percent on total leukocyte gate were CD45(98%),HLA-DR(89%),CD13(10%),CD33(10%),CD14(0.2%) and CD 34(1 %)CD41, CD61, glycophorin A were negative.,. Her chromosomal study result was:48–50,XX,+6,+8,add(8)(p23),+9,ADD(9)(p24),+14[17]/46,XX[3] and didn't show a specific abnormality.Induction chemotherapy was immediately administered. 7 days cytarabine plus 3 days Daunorobicine standard protocol.Copmlete remission was achived on day 28 of induction therapy.After complete remission on day 28 she did not have bone marrow fibrosis anymore. She received consalidation chemotherapy Our consalidation protocol was:cytarabine 100 mg/bid/sq for 5 day and Mitoxantrone 10 mg/M2 day one altrnative with cytarabine 100 mg/bid/sq *5 day with Danarobicin 45 mg/M2 day 1–2 for six courses.At present time after complete consalidation course she is in complete remission with no evidence of disease.

High Serum Levels of Matrix Metalloproteinase-9 and Matrix Metalloproteinase-1 Are Associated with Rapid Progression in Patients with Metastatic Melanoma

Matrix metalloproteinases (MMP) are proteolytic enzymes that play an important role in various aspects of cancer progression. In the present work, we have studied the prognostic significance of serum levels of gelatinase B (MMP-9), collagenase-1 (MMP-1), and collagenase-3 (MMP-13) in patients with advanced melanoma. Total pretreatment serum levels of MMP-9 in 71 patients and MMP-1 and MMP-13 in 48 patients were determined by an assay system based on ELISA. Total MMP levels were also assessed in eight healthy controls. The active and latent forms of MMPs were defined by using Western blot analysis and gelatin zymography. Patients with high serum levels of MMP-9 (> or = 376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n = 52; median OS, 29.1 versus 45.2 months; P = 0.033). High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P = 0.032). Serum levels of MMP-1 and MMP-13 did not correlate with OS. MMP-1 and MMP-9 were found mainly in latent forms in serum, whereas the majority of MMP-13 in serum was active (48 kDa) form. MMP-13 was found more often in active form in patients (mean, 99% of the total MMP-13 level) than in controls (mean, 84% of the total MMP-13 level; P < 0.0001). After initiating the therapy, patients with elevated levels of MMP-1 (> or = 29.8 ng/mL, n = 10) progressed more rapidly than patients with lower levels (median, 1.9 versus 3.5 months; P = 0.023). Serum levels of MMP-9 and MMP-13 did not correlate with the time to progression (TTP). In multivariate analysis with age and gender, MMP-9 or MMP-1 turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confidence interval (95% CI), 1.03-3.3] or TTP (P = 0.023; HR, 2.7; 95% CI, 1.15-6.4), respectively. Our findings provide evidence that MMP-1, MMP-9, and MMP-13 play important roles at different phases of metastatic melanoma spread and that serum MMP-9, in particular, could have clinical value in identifying patients at high risk for melanoma progression.

The natural history of asymptomatic primary biliary cirrhosis

Appreciation of the spectrum of clinical features of primary biliary cirrhosis (PBC) has evolved considerably over the past few decades. Although the substantial female predominance documented in early series remains true today, it has become clear that other so called ‘classical’ clinical features, such as symptoms of jaundice, pruritis and fatigue, and even biochemical markers of cholestasis, need not necessarily be present. Only a small minority of patients nowadays present with liver failure and most are even identified while asymptomatic, with up to 80% of patients in recently reported series having no PBC-related symptoms at the time of diagnosis, compared to only 4% some 30 years ago (Table 1).1–7 The diagnosis of PBC in asymptomatic patients is usually established after the chance finding of an abnormal physical sign, such as hepatomegaly, or, more often, an elevated serum alkaline phosphatase level during the course of an unrelated illness. Alternatively, patients may be diagnosed after biochemical or autoantibody, including anti-mitochondrial antibody (AMA), screening is carried out either as part of a routine health check or following the documentation of one of the many extrahepatic, predominantly autoimmune, disorders known to be associated with PBC. Crucial to the validity of diagnosing PBC on the basis of a positive AMA test in the latter circumstance is the finding that over 93% of AMA-positive yet asymptomatic patients with no biochemical evidence of cholestasis nonetheless have histological changes compatible with (or diagnostic of) PBC at liver biopsy.8 View this table: Table 1 Prevalence of symptoms at diagnosis of PBC Recognition of the extended clinical spectrum of PBC has resulted in a substantial increase in its reported prevalence, at least in some areas. Far from the historical view of PBC as an uncommon condition,9 recent studies from the north-east of England and Olmstead County in the US indicate that … Address correspondence to A/Professor S.M. Riordan, Gastrointestinal and Liver Unit, The Prince of Wales Hospital, Barker Street, Randwick 2031, New South Wales, Australia. email: riordans{at}sesahs.nsw.gov.au

Hepatosplenic Candidiasis in Patients with Acute Leukemia

Hepatosplenic candidiasis (HSC) or chronic disseminated candidiasis (CDC) is an invasive fungal infection that affects neutropenic patients. The Invasive Fungal Infectious Group of the European Organization for Research and Treatment of Cancer (EORTC-IFIG) and the Mycoses Study Group of the National Institute for Allergy and Infectious Diseases (MSG-NIAID) require peripheral, target-like abscesses on liver and/or spleen imaging in addition to elevated serum alkaline phosphatase levels for diagnosis of HSC [1]. Despite this standardized definition, consistent data yielding an estimated incidence is not yet available.

Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure?

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease with a variable clinical course. Identification of serologic markers associated with increased risk of liver failure would assist in management of PBC patients. The objective of this study was to identify antinuclear antibody (ANA) markers that may be used to predict PBC outcome. Indirect immunofluorescence was used to identify ANAs in 492 PBC patients. chi2 and Kaplan-Meier analyses were used to examine the association between ANAs and liver failure. A greater percentage of ANA-positive, compared to ANA-negative, PBC patients developed liver failure (41% vs 25%, P = .005). The presence of anti-centromere antibodies was associated with liver failure (anti-centromere antibody positive vs negative, 58% vs 33%, P = .001). The time to liver failure was shorter in ANA-positive, compared with ANA-negative, patients (log rank score 5.8, P = .02). After 8.9 years (the median follow-up for patients without liver failure), 68% of ANA-positive and 81% of ANA-negative patients were free of liver failure. Anti-centromere antibodies were also associated with a shorter time to liver failure (log rank score 8.4, P = .004). After 8.9 years, 52% of anti-centromere antibody positive and 74% of anti-centromere antibody negative patients were without liver failure. ANAs in general, and anti-centromere antibodies in particular, are associated with liver failure in PBC. PBC patients with ANAs may be candidates for treatment with experimental therapies to prolong the interval between diagnosis and liver failure. ANA-negative patients, who appear to have a relatively benign clinical course, should perhaps be treated with ursodeoxycholic acid alone.

Magnetic resonance cholangiography in the diagnosis of biliary complications after orthotopic liver transplantation

Objective The aim of our study was to evaluate the role of magnetic resonance cholangiography (MRC) in the diagnosis of biliary tract complications (BC) after orthotopic liver transplantation (OLT). Materials and methods Among 21 OLT patients who underwent routine follow-up MRC using a breath-hold T2-weighted turbo spin-echo sequence with half-Fourier acquisition (HASTE), 5 had an elevated serum alkaline phosphatase level. Diagnostic confirmation was obtained with endoscopic retrograde cholangiography (ERC) (n = 11), surgery (n = 3), or clinical and laboratory follow-up of at least 1 year (n = 8). Results In 13 patients, no abnormality of the biliary tract was detected using MRC. In 8 patients, anastomotic strictures were diagnosed, 7 of which were confirmed at surgery or using ERC. One patient with normal findings at MRC and abnormal liver function test results was found to have a stricture at ERC. All patients with normal MRC and liver function tests had 1 year of uneventful follow-up and were considered true-negative cases. We found that MRC had 87.5% sensitivity, 92.3% specificity, 87.5% positive predictive value, 92.3% negative predictive value, and 90.4% accuracy for the diagnosis of BC. Conclusion MRC is a valuable examination to detect BC after OLT. It provides useful information for planning interventional procedures.

A Pilot Study of Etanercept in the Treatment of Primary Sclerosing Cholangitis

There is no effective medical treatment for primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease that usually progresses to cirrhosis and liver failure. The aim of this study was to determine the safety and efficacy of etanercept, an inhibitor of tumor necrosis factor, in the treatment of PSC. Ten patients with clinically active PSC were studied. All had elevated serum alkaline phosphatase levels, cholangiograms that were diagnostic of PSC, and liver histology consistent with PSC. Five patients had elevated serum bilirubin levels, five had pruritus, eight had failed to respond to ursodiol and/or methotrexate, and six had rapidly recurring dominant bile duct strictures. Patients were to receive etanercept, 25 mg subcutaneously twice weekly, for 6 months if there were no side effects and for 1 year if there was evidence of efficacy after 6 months. Biochemical tests of liver function did not improve in any patient. Mean serum bilirubin levels increased significantly, from 2.0 to 3.6 mg/dl (P = 0.026). Two of the five patients with pruritus had resolution of pruritus during treatment with etanercept, recurrence when etanercept was stopped, and resolution when it was restarted, although there was little change in liver enzymes or bilirubin levels. There was no decrease in the rate of stricture formation and there were no side effects. Etanercept, at the dosage used, was well tolerated but not effective in the treatment of PSC. It may be helpful in treating pruritus due to cholestasis.

Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients.

The liver is a common site of amyloid deposition in primary systemic amyloidosis. We reviewed the clinical features and natural history of patients with primary systemic amyloidosis and biopsy-proven hepatic involvement who were evaluated at Mayo Clinic from January 1, 1975, to December 31, 1997. The median age of the study group (68 men; 30 women) was 58.5 years. Seventy-one patients (72%) had involuntary weight loss. Hepatomegaly was found in 79 patients (81%). Eighty-two patients (89%) had proteinuria, and 81 patients (86%) had elevated serum alkaline phosphatase levels. Seventy-six patients (83%) had either a serum or urine monoclonal protein. Before liver biopsy, clinicians considered amyloidosis in the differential diagnosis for only 14 patients (26%). None of our patients experienced hepatic rupture or death due to liver biopsy, and only 4 (4%) bled after liver biopsy. The median survival of the 98 patients was 8.5 months. Predictors of a poor prognosis were congestive heart failure, elevated concentrations of bilirubin, and a platelet count greater than 500 x 109/L. In conclusion, clinicians should consider the diagnosis of primary hepatic amyloidosis in patients who present with involuntary weight loss or hepatomegaly. Other clues to the diagnosis include an unexplained elevated serum alkaline phosphatase level, proteinuria, and evidence for hyposplenism (for example, Howell-Jolly bodies on peripheral blood smear). Liver biopsy was safe. Some patients benefit from systemic chemotherapy.

Systemic Mast Cell Disease Without Associated Hematologic Disorder: A Combined Retrospective and Prospective Study

To study clinicopathologic correlations and identify prognostically important variables in patients with systemic mast cell disease (SMCD) who have no associated hematologic disorders. We identified 40 adult patients with SMCD without associated hematologic disorders. Clinical, laboratory, and bone marrow (BM) histologic findings at the time of referral were evaluated (November 1980-February 2001) for possible correlations with a history of aggressive systemic mastocytosis (retrospectively analyzed) as well as survival (prospectively analyzed). The median follow-up time from diagnosis was 108 months and from BM examination was 24 months. A history of aggressive systemic mastocytosis correlated significantly with increased BM mast cell (MC) content, unfavorable MC infiltration pattern, BM eosinophilia, and elevated serum alkaline phosphatase (SAP) level, but not with BM angiogenesis, reticulin fibrosis, or levels of MC mediators. Of these factors, increased BM MC content and elevated SAP level were also associated with shortened survival from time of referral. This study suggests that the BM MC burden, BM eosinophilia, and SAP level are prognostically important in SMCD without associated hematologic disorders. In contrast, BM angiogenesis, reticulin fibrosis, and levels of MC mediators showed no prognostic relevance.