Clinical manifestations,diagnosis and long-term prognosis of adult autoimmune enteropathy:Experience from Peking Union Medical College Hospital

BACKGROUND Autoimmune enteropathy(AIE)is a rare disease whose diagnosis and long-term prognosis remain challenging,especially for adult AIE patients.AIM To improve overall understanding of this disease’s diagnosis and prognosis.METHODS We retrospectively analyzed the clinical,endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023,whose diagnosis was based on the 2007 diagnostic criteria.RESULTS Diarrhea in AIE patients was characterized by secretory diarrhea.The common endoscopic manifestations were edema,villous blunting and mucosal hyperemia in the duodenum and ileum.Villous blunting(100%),deep crypt lymphocytic infiltration(67%),apoptotic bodies(50%),and mild intraepithelial lymphocytosis(69%)were observed in the duodenal biopsies.Moreover,there were other remarkable abnormalities,including reduced or absent goblet cells(duodenum 94%,ileum 62%),reduced or absent Paneth cells(duodenum 94%,ileum 69%)and neutrophil infiltration(duodenum 100%,ileum 69%).Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies.All patients received glucocorticoid therapy as the initial medication,of which 14/16 patients achieved a clinical response in 5(IQR:3-20)days.Immunosuppressants were administered to 9 patients with indications of steroid dependence(6/9),steroid refractory status(2/9),or intensified maintenance medication(1/9).During the median of 20.5 months of followup,2 patients died from multiple organ failure,and 1 was diagnosed with non-Hodgkin’s lymphoma.The cumulative relapse-free survival rates were 62.5%,55.6%and 37.0%at 6 months,12 months and 48 months,respectively.CONCLUSION Certain histopathological findings,including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies,might be potential diagnostic criteria for adult AIE.The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications,which highlights the need for early diagnosis and novel medications.

Rare extraintestinal manifestations of ulcerative colitis treated with dual biologic therapy:A case report

BACKGROUND Ulcerative colitis(UC)is an idiopathic,chronic inflammatory bowel disease(IBD)most often located in the rectum,but may involve the entire colon.Extra intestinal manifestations(EIMs)occur with varying frequency depending on the affected organ.The most common ones are musculoskeletal EIMs,affecting up to 33%-40%of IBD patients.These include,among others,inflammatory back pain,tendinitis,plantar fasciitis and arthritis.Only a few case reports in literature discuss Achilles tendinitis.CASE SUMMARY This report describes a patient with UC and Achilles tendinitis in whom after many unsuccessful attempts of treatment with sulfasalazine,mesalazine,glucocorticosteroids,infliximab and tofacitinib,a complete UC remission and resolution of Achilles tendinitis were achieved with the use of dual biologic therapy(DBT)-ustekinumab and adalimumab(ADA).CONCLUSION This case mentions rare EIMs of UC and suggests that DBT may be an alternative for patient with ulcerative colitis and EIMs.

Neurological Manifestations of Vitamin B12 Deficiency: About a Case

The authors report a case of deficient sensory neuropathy secondary to vitamin B12 deficiency, diagnosed in the neurology department of the Sino-Central African Friendship University Hospital in Bangui. The diagnosis was made possible by electroneuromyography which showed subclinical neurological damage associated with hematological damage (anemia). Through this observation, we recall the diagnostic criteria of the disease in a context of difficult medical practice. .

Comparison of Oral Manifestations in Hospitalized COVID-19 Positive Patients and COVID-19 Negative Dental Outpatients. A Case Series Study and Literature Review

Background: The Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease, also named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can cause various systemic manifestations that pose a threat to human life. Oral lesions in patients with COVID-19 may appear during or after the illness and may or may not be a consequence of the viral infection. Objective: In this case series we compare the oral manifestations in hospitalized COVID-19 positive patients and COVID-19 negative dental outpatients. Methods: 60 hospitalized COVID-19 patients and 41 control patients, were examined for oral signs and symptoms. The controls were dental patients who visited the hospital for dental care without complaining of any problems related to the oral cavity itself. Results: We have observed a strong association between certain clinical findings and COVID-19, including alterations in taste (ageusia, dysgeusia, and hypogeusia), anosmia, hairy tongue, tongue imprints, red tongue, erythematous candidiasis, pseudomembranous candidiasis, and exfoliative cheilitis. A trend but not statistically significant association at the level of 5% was also noted for colored tongue, linea alba, and pale mucosa. On the contrary, fissured tongue and oral mucosa pigmentation were more frequent in the controls, statistically significant at the level of 5%. Conclusion: COVID-19 has been found to impact the oral cavity, resulting in various oral lesions that can be attributed to either the direct action of the virus or the patient’s immune response.

The relationship between the distribution of HBcAg in liver cells and the pathological manifestations of the liver in 429 HBeAg-positive chronic HBV-infected individuals

Background:The natural history of chronic HBV infection is typically characterized by four stages:the immune tolerance period,the immune clearance period,the immune control period,and the immune escape period.These stages are associated with the distribution of HBcAg in liver cells;however,this relationship remains a topic of broad debate within the field of liver disease.To objectively and quantitatively measure the intracellular distribution of HBcAg,this paper aims to design a method referred to as the“layered evaluation method”and to examine its validation.Methods:The distribution of HBcAg in liver cells is assessed using Image Pro Plus image processing software,along with calculations of cytoplasmic and nuclear positive staining rates.Results:The findings indicate that the highest proportion of patients exhibited a positive cytoplasmic expression rate ranging from 0-2.5%.More than 40% of the total sample was categorized within the 0-2.5% positive nuclear expression range.The HBcAg cytoplasmic positive staining rates were classified into five levels:a cytoplasmic HBcAg positive staining rate of less than 0.05% is designated as level 0,indicating negative expression;a staining rate between 0.05% and 5% is classified as level 1;a rate from 5% to less than 10% is classified as level 2;a rate from 10% to less than 20% is classified as level 3;and a nuclear positivity rate exceeding 20% is classified as level 4.Conclusion:The inflammatory activity grade in these patients was positively correlated with the cytoplasmic distribution of HBcAg.Furthermore,the nuclear distribution rate of HBcAg was significantly higher in the G3 group compared to the other groups.

Coagulation abnormalities and their relationship with bleeding manifestations in patients with dengue-A single center observational study

Objective:To evaluate coagulation abnormalities and their relationship with bleeding manifestations among patients with dengue.Methods:This observational study was conducted on 292 adult dengue patients who were admitted to a tertiary care hospital of Western India from July 2021 to June 2022.Coagulation tests including prothrombin time(PT),international normalized ratio(INR),activated partial thromboplastin time(aPTT),fibrinogen,and D-dimer were performed.Patients were monitored for bleeding manifestations.Results:Coagulation abnormalities were reported in 42.8%of the patients.Overall,prolonged aPTT was the most common coagulation abnormality(40.8%),followed by low fibrinogen(38.7%),raised D-dimer(31.2%),raised INR(26.0%)and prolonged PT(19.2%).Bleeding manifestations were present in 19.9%patients.PT,INR,aPTT and D-dimer levels were significantly higher(P<0.01)and fibrinogen level was significantly lower(P<0.001)in patients with bleeding compared to patients without bleeding.Patients with bleeding had a significantly higher rate of all coagulation abnormalities than patients without bleeding(P<0.01).Conclusions:Patients with bleeding showed a significantly higher frequency of coagulation abnormalities compared to patients without bleeding.Patients with dengue should be assessed for coagulation abnormalities.

Pathogenesis,clinical manifestations,diagnosis,and treatment progress of achalasia of cardia

Achalasia cardia,type of esophageal dynamic disorder,is a relatively rare primary motor esophageal disease characterized by the functional loss of plexus ganglion cells in the distal esophagus and lower esophageal sphincter.Loss of function of the distal and lower esophageal sphincter ganglion cells is the main cause of achalasia cardia,and is more likely to occur in the elderly.Histological changes in the esophageal mucosa are considered pathogenic;however,studies have found that inflammation and genetic changes at the molecular level may also cause achalasia cardia,resulting in dysphagia,reflux,aspiration,retrosternal pain,and weight loss.Currently,the treatment options for achalasia focus on reducing the resting pressure of the lower esophageal sphincter,helping to empty the esophagus and relieve symptoms.Treatment measures include botulinum toxin injection,inflatable dilation,stent insertion,and surgical myotomy(open or laparoscopic).Surgical procedures are often subject to controversy owing to concerns about safety and effectiveness,particularly in older patients.Herein,we review clinical epidemiological and experimental data to determine the prevalence,pathogenesis,clinical presentation,diagnostic criteria,and treatment options for achalasia to support its clinical management.

Liver manifestations in COVID-19 patients:A review article

The coronavirus disease 2019(COVID-19)initially presented as a disease that affected the lungs.Then,studies revealed that it intricately affected disparate organs in the human body,with the liver being one of the most affected organs.This review aimed to assess the association between COVID-19 and liver function,shedding light on its clinical implication.However,its exact pathophysiology remains unclear,involving many factors,such as active viral replication in the liver cells,direct cytotoxic effects of the virus on the liver or adverse reactions to viral antigens.Liver symptoms are mild-to-moderate transaminase elevation.In some patients,with underlying liver disease,more serious outcomes are observed.Thus,liver function should be meticulously considered in patients with COVID-19.

Hepatobiliary manifestations following two-stages elective laparoscopic restorative proctocolectomy for patients with ulcerative colitis:A prospective observational study

BACKGROUND Hepatobiliary manifestations occur in ulcerative colitis(UC)patients.The effect of laparoscopic restorative proctocolectomy(LRP)with ileal pouch anal anastomosis(IPAA)on hepatobiliary manifestations is debated.AIM To evaluate hepatobiliary changes after two-stages elective laparoscopic restorative proctocolectomy for patients with UC.METHODS Between June 2013 and June 2018,167 patients with hepatobiliary symptoms underwent two-stage elective LRP for UC in a prospective observational study.Patients with UC and having at least one hepatobiliary manifestation who underwent LRP with IPAA were included in the study.The patients were followed up for four years to assess the outcomes of hepatobiliary manifestations.RESULTS The patients'mean age was 36±8 years,and males predominated(67.1%).The most common hepatobiliary diagnostic method was liver biopsy(85.6%),followed by Magnetic resonance cholangiopancreatography(63.5%),Antineutrophil cytoplasmic antibodies(62.5%),abdominal ultrasonography(35.9%),and Endoscopic retrograde cholangiopancreatography(6%).The most common hepatobiliary symptom was Primary sclerosing cholangitis(PSC)(62.3%),followed by fatty liver(16.8%)and gallbladder stone(10.2%).66.4%of patients showed a stable course after surgery.Progressive or regressive courses occurred in 16.8%of each.Mortality was 6%,and recurrence or progression of symptoms required surgery for 15%.Most PSC patients(87.5%)had a stable course,and only 12.5%became worse.Two-thirds(64.3%)of fatty liver patients showed a regressive course,while one-third(35.7%)showed a stable course.Survival rates were 98.8%,97%,95.8%,and 94%at 12 mo,24 mo,36 mo,and at the end of the follow-up.CONCLUSION In patients with UC who had LRP,there is a positive impact on hepatobiliary disease.It caused an improvement in PSC and fatty liver disease.The most prevalent unchanged course was PSC,while the most common improvement was fatty liver disease.

Polyneuropathy organomegaly endocrinopathy M-protein and skin changes syndrome with ascites as an early-stage manifestation:A case report

BACKGROUND Polyneuropathy organomegaly endocrinopathy M-protein and skin changes(POEMS)syndrome is a rare paraneoplastic syndrome caused by a potential plasma cell tumor.The clinical manifestations of POEMS syndrome are diverse.Due to the insidious onset and lack of specific early-stage manifestations,POEMS syndrome is easily misdiagnosed or never diagnosed,leading to delayed treatment.Neurological symptoms are usually the first clinical manifestation,while ascites is a rare symptom in patients with POEMS syndrome.CASE SUMMARY A female patient presented with unexplained ascites as an initial symptom,which is a rare early-stage manifestation of the condition.After 1 year,the patient gradually developed progressive renal impairment,anemia,polyserosal effusion,edema,swollen lymph nodes on the neck,armpits,and groin,and decreased muscle strength of the lower extremities.The patient was eventually diagnosed with POEMS syndrome after multidisciplinary team discussion.Treatment comprised bortezomib+dexamethasone,continuous renal replacement therapy,chest and abdominal closed drainage,transfusions of erythrocytes and platelets,and other symptomatic and supportive treatments.The patient’s condition initially improved after treatment.However,then her symptoms worsened,and she succumbed to the illness and died.CONCLUSION Ascites is a potential early manifestation of POEMS syndrome,and this diagnosis should be considered for patients with unexplained ascites.Furthermore,multidisciplinary team discussion is helpful in diagnosing POEMS syndrome.

Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients

AIM: To investigate prevalence, type and time of onset of extraintestinal manifestations (EIMs) in a series of Italian inflammatory bowel disease (IBD) patients.

Neurological manifestations of hepatitis E virus infection:An overview

Hepatitis E virus(HEV)is an important cause of repeated waterborne outbreaks of acute hepatitis.Recently,several extrahepatic manifestations(EHMs)have been described in patients with HEV infection.Of these,neurological disorders are the most common EHM associated with HEV.The involvement of both the peripheral nervous system and central nervous system can occur together or in isolation.Patients can present with normal liver function tests,which can often be misleading for physicians.There is a paucity of data on HEV-related neurological manifestations;and these data are mostly described as case reports and case series.In this review,we analyzed data of 163 reported cases of HEV-related neurological disorders.The mechanisms of pathogenesis,clinico-demographic profile,and outcomes of the HEV-related neurological disorders are described in this article.Nerve root and plexus disorder were found to be the most commonly reported disease,followed by meningoencephalitis.

COVID-19 status quo:Emphasis on gastrointestinal and liver manifestations

The coronavirus disease 2019(COVID-19)has caused one of the worst public health crises in modern history.Even though severe acute respiratory syndrome coronavirus 2 primarily affects the respiratory tract,gastrointestinal manifestations are well described in literature.This review will discuss the epidemiology,virology,manifestations,immunosuppressant states,and lessons learned from COVID-19.Observations:At the time of writing,COVID-19 had infected more than 111 million people and caused over 2.5 million deaths worldwide.Multiple medical comorbidities including obesity,pre-existing liver condition and the use of proton pump inhibitor have been described as risk factor for severe COVID-19.COVID-19 most frequently causes diarrhea(12.4%),nausea/vomiting(9%)and elevation in liver enzymes(15%-20%).The current data does not suggest that patients on immunomodulators have a significantly increased risk of mortality from COVID-19.The current guidelines from American Gastroenterological Association and American Association for the Study of Liver Diseases do not recommend pre-emptive changes in patients on immunosuppression if the patients have not been infected with COVID-19.Conclusions and relevance:The COVID-19 pandemic has prompted a change in structure and shape of gastroenterology departmental activities.Endoscopy should be performed only when necessary and with strict protective measures.Online consultations in the form of telehealth services and home drug deliveries have revolutionized the field.

Effect of treating chronic hepatitis C with direct-acting antivirals on extrahepatic cutaneous manifestations

BACKGROUND Hepatitis C virus(HCV)is a disease with a significant global impact,affecting approximately 2%-2.5%of the world’s population.New direct-acting antivirals(DAAs)have been introduced over the past few years with great success in viral eradication.The association of chronic HCV infection with a wide spectrum of cutaneous manifestations has been widely reported in the literature.AIM To assess the effect of treating HCV with DAAs on the extrahepatic cutaneous manifestations of HCV.METHODS This prospective observational study included 1039 HCV positive Egyptian patients who were eligible to receive DAAs.A total of 30 patients were diagnosed with extrahepatic cutaneous manifestations and fulfilled the inclusion criteria of the study.Of these patients,6 had classic lichen planus,8 were diagnosed with psoriasis vulgaris and 16 had pruritus.All patients received DAAs from October 2018 to July 2019 in the form of a three-month course of sofosbuvir/daclatasvir combination.Patients with lichen planus or psoriasis were dermoscopically evaluated before treatment and 6 mo after treatment,while patients with hepatic pruritus were assessed using the 12-Item Pruritus Severity Scale over the same period.RESULTS All patients with psoriasis showed significant improvement in all psoriatic plaques,and all patients with hepatic pruritus scored 0 on the 12-Item Pruritus Severity Scale indicating total improvement of pruritus.In addition,four of six patients with lichen planus showed complete improvement.CONCLUSION Treatment of HCV with DAAs was significantly effective in improving virusrelated extrahepatic cutaneous manifestations.

Analysis of Manifestations of and Solutions to Chinglish

Chinglish often occurs in the process of English language acquisition.It’s necessary to clarify what Chinglish is and what the major features are.The paper elaborates five major manifestations of Chinglish in terms of phonological difference,lexical redundancy and word misuse,unreasonable sentence structure as well as semantic misuse,and then proposes solutions to Chinglish through improvement of linguistic competence,conversion of thinking modes and enhancement of the awareness of cultural factors.

Osteoarticular manifestations of human brucellosis:A review

Brucellosis is a common global zoonotic disease, which is responsible for a range of clinical manifestations. Fever, sweating and musculoskeletal pains are observed in most patients. The most frequent complication of brucellosis is osteoarticular involvement, with 10% to 85% of patients affected. The sacroiliac(up to 80%) and spinal joints(up to 54%) are the most common affected sites.Spondylitis and spondylodiscitis are the most frequent complications of brucellar spinal involvement. Peripheral arthritis, osteomyelitis, discitis, bursitis and tenosynovitis are other osteoarticular manifestations, but with a lower prevalence. Spinal brucellosis has two forms: focal and diffuse. Epidural abscess is a rare complication of spinal brucellosis but can lead to permanent neurological deficits or even death if not treated promptly. Spondylodiscitis is the most severe form of osteoarticular involvement by brucellosis, and can have single-or multifocal involvement. Early and appropriate diagnosis and treatment of the disease is important in order to have a successful management of the patients with osteoarticular brucellosis. Brucellosis should be considered as a differential diagnosis for sciatic and back pain, especially in endemic regions. Patients with septic arthritis living in endemic areas also need to be evaluated in terms of brucellosis. Physical examination, laboratory tests and imaging techniques are needed to diagnose the disease. Radiography, computed tomography, magnetic resonance imaging(MRI) and bone scintigraphy are imaging techniques for the diagnosis of osteoarticular brucellosis. MRI is helpful to differentiate between pyogenic spondylitis and brucellar spondylitis. Drug medications(antibiotics)and surgery are the only two options for the treatment and cure of osteoarticular brucellosis.

Scrub typhus:pathophysiology,clinical manifestations and prognosis

Scrub typhus is a zoonosis caused by the pathogen Orientia tsutsugamushi(O.tsvtsugamushi). The disease has significant prevalence in eastern and Southeast Asia.Usually presenting as an acute febrile illness,the diagnosis is often missed because of similarities with oilier tropical febrile infections.Many unusual manifestations are present,and these are described in this review,together with an outline of current knowledge of pathophysiology.Awareness of these unusual clinical manifestations will help the clinician to arrive at an early diagnosis,resulting in early administration of appropriate antibiotics.Prognostic indicators for severe disease have not yet been clearly established.

Hepatobiliary manifestations in inflammatory bowel disease: The gut,the drugs and the liver

Abnormal liver biochemical tests are present in up to30%of patients with inflammatory bowel disease(IBD),and therefore become a diagnostic challenge.Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis(UC),and typically do not correlate with intestinal activity.Primary sclerosing cholangitis(PSC)is the most common hepatobiliary manifestation of IBD,and is more prevalent in UC.Approximately 5%of patients with UC develop PSC,with the prevalence reaching up to 90%.Cholangiocarcinoma and colon cancer risks are increased in these patients.Less common disorders include autoimmune hepatitis/PSC overlap syndrome,IgG4-associated cholangiopathy,primary biliary cirrhosis,hepatic amyloidosis,granulomatous hepatitis,cholelithiasis,portal vein thrombosis,liver abscess,and non-alcoholic fatty liver disease.Hepatitis B reactivation during immunosuppressive therapy is a major concern,with screening and vaccination being recommended in serologically negative cases for patients with IBD.Reactivation prophylaxis with entecavir or tenofovir for 6to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen(HBsAg)positive,independently from viral load.HBsAg negative and anti-HBc positive patients,with or without anti-HBs,should be closely monitored,measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy,and should be treated if the viral load increases.On the other hand,immunosuppressive therapy does not seem to promote reactivation of hepatitis C,and hepatitis C antiviral treatment does not influence IBD natural history either.Most of the drugs used for IBD treatment may induce hepatotoxicity,although the incidence of serious adverse events is low.Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant.Methotrexaterelated hepatotoxicity has been described in 14%of patients with IBD,in a dose-dependent manner.Liver biopsy is not routinely recommended.Biologics-related hepatotoxicity is rare,but has been shown most frequently in patients treated with infliximab.Thiopurines have been associated with veno-occlusive disease,regenerative nodular hyperplasia,and liver peliosis.Routine liver biochemical tests are recommended,especially during the first month of treatment.All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement.Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.

Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment

The hepatitis E virus(HEV)is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s.Globally,it is one of the most frequent causes of acute viral hepatitis.The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus.Among the eight different genotypes identified to date,HEV genotype 1(HEV1),HEV2,HEV3,and HEV4 are the most frequent genotypes causing infections in humans.HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies.They are also responsible for severe hepatitis in pregnant patients and infants.In contrast,HEV3 and HEV4 are zoonotic,and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals.Their main reservoir is the pig,and they are mostly encountered in developed countries.The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women,infants,older people,immunocompromised individuals,patients with underlying chronic liver diseases,and workers that come into close contact with HEV-infected animals.In the clinical perspective,HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis,acute-on-chronic liver disease,chronic hepatitis,cirrhosis,and liver failure.Although HEV mainly results in acute selflimiting infection,chronic HEV infection may occur among immunocompromised patients(e.g.,solid-organ transplant recipients).Additionally,HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade,although the causal link for many of them still needs to be proven.Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success.However,ribavirin is contraindicated in pregnant patients,and interferon-alpha cannot be used in most transplant recipients.Therefore,there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirinresistant HEV.In this review article,a literature search using PubMed and MEDLINE databases was performed,up to March 2020.Only the articles published in English were reviewed.

Extraintestinal manifestations and complications in inflammatory bowel diseases

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory bowel diseases （IBD） that often involve organs other than those of the gastrointestinal tract. These nonintestinal affections are termed extraintestinal symptoms. Differentiating the true extraintestinal manifestations of inflammatory bowel diseases from secondary extraintestinal complications, caused by malnutrition, chronic inflammation or side effects of therapy, may be difficult. This review concentrates on frequency, clinical presentation and therapeutic implications of extraintestinal symptoms in inflammatory bowel diseases. If possible, extraintestinal manifestations are differentiated from extraintestinal complications. Special attention is given to the more recently described sites of involvement; i.e. thromboembolic events, osteoporosis, pulmonary involvement and affection of the central nervous system.