Hepatobiliary Manifestations Research Articles

English

Hepatobiliary diseases occur commonly in patients with Human immunodeficiency virus (HIV) infection and are now the commonest cause of death in HIV positive patients on antiretroviral therapy (ART) in western countries. The hepatobiliary manifestations of AIDS are related to the levels of CD4+ count as well as liver enzymes. Abdominal ultrasound examination is easy to perform, non-invasive, inexpensive, readily available and provides valuable information about hepatobiliary findings in AIDS. The study was to evaluate hepatobiliary sonographic findings in HIV/AIDS adult patients and correlate with their CD4+ count and abnormal liver enzymes (ALP, ALT and AST) in Jos, Plateau State, Nigeria. A cross-sectional study of hepatobiliary ultrasound findings of 410 adult patients with HIV/AIDS was carried out over a period of six months. Two hundred and sixteen (52.7%) of the patients had normal hepatobiliary ultrasound findings while 194 (47.3%) patients had various abnormalities. The common abnormalities seen include enlarged gallbladder in 33.5%, increased liver parenchymal echogenicity in 26.3%, hepatomegaly in 23.7%, and thickened gallbladder wall in 7.8% patients. Other findings included gallbladder sludge and gall stone in 6.6 and 2.1% respectively. These findings correlated significantly with the patients’ CD4+ count and liver enzymes (ALT, AST and ALP) with p value < 0.05 in both. Ultrasonography as a baseline imaging modality in HIV/AIDS patients, together with CD4+ count and liver enzymes are useful in the assessment of the disease state, monitoring of therapy and management of these patients. Key words: Hepatobiliary ultrasonography, adult patients, CD4 cell count, HIV/AIDS, liver enzymes.

SCIC (Sickle Cell Intrahepatic Cholestasis) Patient with Acute Liver Failure

Sickle cell disease may cause of variety of hepatobiliary manifestations. Intrahepatic cholestasis is a rare but potentially lethal complication which has been reported to improve with exchange transfusion. We present a case of an elderly man with acute liver failure due to SCIC who passed despite exchange transfusion (ET). This is a 64 year old man with Hemoglobin S/B thalassemia, hypertension, and end-stage renal disease (ESRD) on hemodialysis who initially presented fever, vomiting, and icterus. No abdominal pain or altered mental status (AMS) was noted on physical exam. He did not take any hepatotoxic medication or supplements. Initial labs were significant for total bilirubin of 20 with direct bilirubin >10, hemoglobin of 6.8 with hemoglobin S % of 78.7, AST of 109, ALT 18, LDH of 1080 and haptoglobin <30. Viral hepatitis serologies were negative. Abdominal ultrasound was negative for choledocholithiasis and demonstrated patent hepatic vessels (Image 1). CT of the abdomen was also negative other than hepatomegaly (Image 2). The patient was initially given supportive treatment. The total bilirubin continued to rise and peaked at 53 and INR rose to 3.2. Alkaline Phosphatase was 180 and GGT was 90. Patient developed AMS and tender hepatomegaly. Patient was sent for exchange transfusion with HbS concentration decrease to less than <30%. Despite exchange transfusion, the patient continued to decompensate and eventually succumbed to the disease. There are several case reports of patients with SCIC who have responded to exchange transfusion however there are also cases of patients responding to supportive treatment alone. Our patient, however, did not respond despite exchange transfusion, suggesting that advanced age and chronic renal disease may have a negative impact on overall prognosis. He was not a candidate for liver transplantation. Based on the literature, it seems he is the oldest patient and the only one with ESRD thus far reported to develop SCIC. He did not receive exchange transfusion until a few days after admission thus the delay in exchange transfusion may have contributed to his lack of improvement. Early initiation of exchange transfusion should be considered in patients with evidence of hepatic failure from intrahepatic cholestasis. Future studies need to be done to determine appropriate timing and HbS concentration goals to improve outcomes in this potentially fatal disease.2355_A Figure 1 No Caption available.2355_B Figure 2 No Caption available.

Development of deep neural network for individualized hepatobiliary toxicity prediction after liver SBRT.

Accurate prediction of radiation toxicity of healthy organs-at-risks (OARs) critically determines the radiation therapy (RT) success. The existing dose-volume histogram-based metric may grossly under/overestimate the therapeutic toxicity after 27% in liver RT and 50% in head-and-neck RT. We propose the novel paradigm for toxicity prediction by leveraging the enormous potential of deep learning and go beyond the existing dose/volume histograms. We employed a database of 125 liver stereotactic body RT (SBRT) cases with follow-up data to train deep learning-based toxicity predictor. Convolutional neural networks (CNNs) were applied to discover the consistent patterns in 3D dose plans associated with toxicities. To enhance the predicting power, we first pretrain the CNNs with transfer learning from 3D CT images of 2644 human organs. CNNs were then trained on liver SBRT cases. Furthermore, nondosimetric pretreatment features, such as patients' demographics, underlying liver diseases, liver-directed therapies, were inputted into the fully connected neural network for more comprehensive prediction. The saliency maps of CNNs were used to estimate the toxicity risks associated with irradiation of anatomical regions of specific OARs. In addition, we applied machine learning solutions to map numerical pretreatment features with hepatobiliary toxicity manifestation. Among 125 liver SBRT patients, 58 were treated for liver metastases, 36 for hepatocellular carcinoma, 27 for cholangiocarcinoma, and 4 for other histologies. We observed that CNN we able to achieve accurate hepatobiliary toxicity prediction with the AUC of 0.79, whereas combining CNN for 3D dose plan analysis and fully connected neural networks for numerical feature analysis resulted in AUC of 0.85. Deep learning produces almost two times fewer false-positive toxicity predictions in comparison to DVH-based predictions, when the number of false negatives, i.e., missed toxicities, was minimized. The CNN saliency maps automatically estimated the toxicity risks for portal vein (PV) regions. We discovered that irradiation of the proximal portal vein is associated with two times higher toxicity risks (risk score: 0.66) that irradiation of the left portal vein (risk score: 0.31). The framework offers clinically accurate tools for hepatobiliary toxicity prediction and automatic identification of anatomical regions that are critical to spare during SBRT.

Colecistopatia aguda calculosa como manifestação extraintestinal em paciente com doença de Crohn: relato de caso

A doença de Crohn (DC) é uma patologia inflamatória intestinal de etiologia desconhecida que acomete o trato gastrointestinal e pode afetar outros órgãos, como, por exemplo, a vesícula biliar. Entre as manifestações hepatobiliares, os pacientes podem apresentar colecistite, colelitíase, colangite. A associação entre DC e colelitíase é bem estabelecida, sendo esses pacientes são mais propensos a desenvolver colelitíase, devido à alteração na composição da bile e a uma redução da motilidade da vesícula biliar. Descrevemos um caso em que uma paciente com doença de Crohn apresentou colelitíase.

Pathogenesis of immunoglobulin G4-related hepatobiliary disease

IgG4-relaed hepatobiliary diseases (IgG4-HBD) are the hepatobiliary manifestations of IgG4-related disease, a multisystem fibro-inflammatory disorder. Previous studies on the pathogenesis of genetics and immunology have provided significant assistance in understanding the disease, rational diagnosis and treatment, but there are still many unknowns and challenges. The current research progress summarizes several factors influencing fibrosis and inflammation in the pathogenesis of disease.

IgG4-associated cholangitis - clinical presentation of an overlooked disease entity

IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease, which is an immune-mediated fibroinflammatory systemic disorder characterised by often elevated IgG4 serum levels and typical histopathological findings in affected tissues. IAC is frequently (>90%) accompanied by autoimmune pancreatitis type1 (AIP), which is the pancreatic manifestation of immunoglobulin G4-related disease. In 80-85% of the cases patients with IAC are male, above 50years of age and present with jaundice and weight loss. Aremarkable percentage of patients with IAC has ahistory of long-term exposure to solvents, oil products and other organic agents representing so-called "blue-collar workers". Clinical features and imaging (i. e. strictures or mass-forming lesions in the biliary tract) may mimic other biliary diseases, such as primary or secondary sclerosing cholangitis and cholangiocarinoma. The HISORt criteria are used for diagnosing IAC and comprise histologic and imaging findings, serum IgG4, organ manifestation pattern and response to immunosuppressive therapy. Serum IgG4 levels are of diagnostic value when it is above 4times the upper limit of normal. Determination of the blood IgG4/IgG mRNA ratio using quantitative polymerase chain reaction (qPCR) is an accurate diagnostic tool currently under clinical validation. The majority of patients show an excellent response to corticosteroid therapy. Symptom recurrence, however, is common making long-term treatment with low-dose prednisolone and/or azathioprine frequently necessary.

Hepatobiliary Manifestations and Complications in Inflammatory Bowel Disease: A Review.

Liver and biliary track diseases are common extraintestinal manifestations of inflammatory bowel disease (IBD), reported both in Crohn’s disease and ulcerative colitis, and may occur at any time during the natural course of the disease. Their etiology is mainly related to pathophysiological changes induced by IBD, and secondary, due to drugs used in IBD. Fatty liver is considered as the most frequent hepatobiliary manifestation in IBD, while primary sclerosing cholangitis (PSC) is the most correlated hepatobiliary disorder and is more prevalent in patients with ulcerative colitis. PSC can cause serious complications from the liver, biliary tree, and gallbladder and can lead to liver failure. Less frequently, IBD-associated hepatobiliary manifestations include cholelithiasis, granulomatous hepatitis, portal vein thrombosis, IgG4-related cholangiopathy, pyogenic liver abscess, hepatic amyloidosis and primary biliary cirrhosis. Most of the drugs used for IBD treatment may cause liver toxicity. Methotrexate and thiopurines carry the higher risk for hepatotoxicity, and in many cases, dose adjustment may normalize the liver biochemical tests. Reactivation of hepatitis B and C virus during immunosuppressive use, especially during use of biological agents, is a major concern, and adequate screening, vaccination and prophylactic treatment is warranted.

Cystic Fibrosis: Clinical Phenotypes in Children and Adolescents.

PurposeThe objective of this study was to describe the clinical phenotypes of children and adolescents with cystic fibrosis (CF); and to assess the role of pancreatic insufficiency and neonatal screening in diagnosis.MethodsA cross-sectional study was conducted, which included 77 patients attending a reference center of CF between 2014 and 2016. Epidemiological data, anthropometric measurements, and the presence of pulmonary, pancreatic, gastrointestinal and hepatobiliary manifestations were evaluated based on clinical data and complementary examinations.ResultsOf the 77 patients, 51.9% were male, with a median age of 147 months (7.0–297.0 months), and the majority showed adequate nutritional status. The most common phenotype was pulmonary (92.2%), followed by pancreatic (87.0%), with pancreatic insufficiency in most cases. Gastrointestinal manifestation occurred in 46.8%, with constipation being the more common factor. Hepatobiliary disease occurred in 62.3% of patients. The group with pancreatic insufficiency was diagnosed earlier (5.0 months) when compared to the group with sufficiency (84.0 months) (p=0.01). The age of diagnosis was reduced following implementation of neonatal screening protocols for CF (6.0 months before vs. 3.0 months after, p=0.02).ConclusionThe pulmonary phenotype was the most common, although extrapulmonary manifestations were frequent and clinically relevant, and should mandate early detection and treatment. Neonatal screening for CF led to earlier diagnosis in patients with pancreatic failure, and therefore, should be adopted universally.

Cystic Fibrosis in Childhood and Adolescence

Although cystic fibrosis (CF) has historically been considered a pulmonary disease, with the increasing life expectancy of these patients, gastrointestinal manifestations are becoming more important. Moreover, nutritional status is closely linked to pulmonary function and, thus, overall mortality. This review discusses gastrointestinal (including nutritional, pancreatic, and hepatobiliary) manifestations of CF and their management. It also discusses studies that have been critical to our understanding of these manifestations of CF. This review contains 1 figure, 1 table, and 36 references. Key words: body mass index, constipation, cystic fibrosis transmembrane regulator, distal intestinal obstruction syndrome, pancreatic insufficiency

Cystic Fibrosis in Childhood and Adolescence

Although cystic fibrosis (CF) has historically been considered a pulmonary disease, with the increasing life expectancy of these patients, gastrointestinal manifestations are becoming more important. Moreover, nutritional status is closely linked to pulmonary function and, thus, overall mortality. This review discusses gastrointestinal (including nutritional, pancreatic, and hepatobiliary) manifestations of CF and their management. It also discusses studies that have been critical to our understanding of these manifestations of CF. This review contains 1 figure, 1 table, and 36 references. Key words: body mass index, constipation, cystic fibrosis transmembrane regulator, distal intestinal obstruction syndrome, pancreatic insufficiency

Increased cholestatic enzymes in two patients with long-term history of ulcerative colitis: consider primary biliary cholangitis not always primary sclerosing cholangitis

Several hepatobiliary disorders have been reported in ulcerative colitis (UC) patients with primary sclerosing cholangitis (PSC) being the most specific. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis,...

Histologically proved cytomegalovirus as a terrible and neglect disease: a 13-year report of gastrointestinal and hepatobiliary manifestations from single referral center

The aim of the present study was to evaluate the gastrointestinal and hepatobiliary manifestation of cytomegalovirus. In a retrospective study, demographic and clinical information of patients with gastrointestinal or hepatobiliary manifestations and histologically confirmed cytomegalovirus infection was investigated among pathological records. The association between serum cytomegalovirus pp65 and blood positivity of cytomegalovirus polymerase chain reaction with histological findings was also evaluated. Of the 74 included patients, 27 cases (36.5%) were female. The most common symptoms were diarrhea (24.3%). Unusual presentations of cytomegalovirus diseases were gastrointestinal obstruction, refractory peptic ulcer, and corticosteroid-refractory inflammatory bowel disease. In total, 54 cases (75.0%) were transplanted, with the most frequency of kidney transplantation in 32 patients (59.2%). These patients had also more mortality rate. The most prescribed medicine in transplanted patients was CellCept and cyclosporine (40.6%). Mortality rate was more in blood polymerase chain reaction-negative patients. Cytomegalovirus diseases in transplanted patients were more primary infection compared with reactivation infection. No significant difference in mortality rate was seen between ganciclovir and non-ganciclovir recipients. The majority of the patients were negative for antigen or polymerase chain reaction. Early detection of cytomegalovirus could be lifesaving, and negative results of antigen and polymerase chain reaction cannot rule out cytomegalovirus diseases. Early endoscopic evaluation for unusual presentations of cytomegalovirus disease and also liver donor evaluation should be done more carefully. Ganciclovir has no significant effect on mortality of the patients, and then, it should be started at appropriate time.

Gut-liver axis in inflammatory bowel disease. A retrospective study

Examination of the gut-liver axis came into the spotlight worldwide. Liver enzyme elevations are commonly seen in patients with inflammatory bowel disease (IBD), which is a diagnostic challenge in everyday clinical practice. Liver and biliary diseases are common extra-intestinal manifestations in Crohn's disease and ulcerative colitis. The assessment of routine liver function tests could be an inaccurate reflection of liver damage, so its prevalence could be underestimated. There would be a need for non-invasive biomarkers and/or scoring systems, which would help the diagnosis of liver damage associated with intestinal diseases. In our work we considered to highlight the importance of the gut-liver axis significance. We used data of patients suffering from ulcerative colitis, as a model for bowel diseases to understand the underlying factors of the pathogenesis of hepatobiliary manifestations. In our retrospective study, we investigated the data of 100 ulcerative colitis patients (male = 46, female = 54) (mean age: 42.5 ± 12.7) and compared to healthy controls (n = 42) (male = 17, female = 25) (mean age: 40.2 ± 13.5). Liver function tests (ALT, AST, GGT, ALP, bilirubin, albumin, thrombocyte), bile acid levels were determinated, and various free radical markers (global, enzymatic) were used to assess the redox homeostasis of patients. Hydrogen donor activity, reducing power, superoxide dismutase and glutathione peroxidase activity, total antioxidant status and induced chemiluminescence were measured, considering that the patients received 5-aminosalicilate and/or azathioprin and elemental diet treatment. Liver function parameters were increased in ulcerative colitis patients, and total antioxidant status, as well. Reducing power significantly decreased, but there was no significant difference compared to the control group of glutathione peroxidase and H-donor activity, we observed only tendentious decrease. The antioxidant protection of more than 54% of patients had a significantly lower rate, according to all the parameters. With chemiluminescence measurement we measured better free radical scavenging capacity, both in plasma and in erythrocytes as a result of the therapy, however, it showed an increase of superoxide dismutase activity, which warns of inflammatory processes. The cause of the decrease in bile acid levels found in the group of ulcerative colitis patients, can be the accelerated peristaltic. In the daily routine, liver enzyme values do not give an accurate picture of liver damage associated with ulcerative colitis. With the help of various specific parameters determined by us, we can estimate the background processes of the gut-liver axis alterations. The decrease in bile acid levels can be a predictive factor in ulcerative colitis. Our work highlights the need of non-invasive screening for liver diseases in inflammatory bowel disease. Orv Hetil. 2017; 158(26): 1014-1021.

Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner

ObjectivePrimary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion...

Kako prepoznati i lečiti pacijenta sa inflamatornim bolestima creva

Inflammatory bowel diseases (IBD) are idiopathic, chronic intestinal inflammatory diseases. IBD pathogenesis is related to altered immune response and its complex interaction with gut microbiota, genetic and environmental factors. Most common types of IBD are ulcerative colitis (UC) and Crohns disease (CD), while a subset of patients suffer from undetermined IBD. Ulcerative colitis is chronic inflammatory disease limited to colonic musoa. As opposed to UC, CD is chronic granulomatous disease that can affect any segment of the gastrointestinal tract and all layers of bowel wall. Extraintestinal manifestations of IBD include musculoskeletal, dermatological, ocular and hepatobiliary manifestations. IBD diagnosis is based on clinical presentation, laboratory findings, endoscopic procedures with patohistological examination of tissue biopsies. In some patients additional radiographic diagnostic tools are needed. Therapy in IBD patients is based on the use of mesalamines and sulphasalazyne, corticosteroids, immunomodulators, biologic therapy and surgery. Mesalamines are used as induction therapy in UC patients, while corticosteroids and biologic therapy can be used as induction therapy in both UC and CD patients. Maintenance therapy in UC consists of mesalamines, thiopurines and biologics, while in CD thiopurines, methotrexate and biologics can be used. In pediatric patients nutritional therapy can be beneficial.

Primary sclerosing cholangitis in the Swiss Inflammatory Bowel Disease Cohort Study: prevalence, risk factors, and long-term follow-up.

Primary sclerosing cholangitis (PSC) represents the most common hepatobiliary extraintestinal manifestation of inflammatory bowel disease (IBD). We aimed to assess the prevalence of PSC in the Swiss Inflammatory Bowel Disease Cohort Study, to identify associated risk factors, and to describe the long-term evolution. Data of patients enrolled into the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. Logistic regression modeling was performed to identify risk factors for PSC. Among 2744 patients [1188 ulcerative colitis (UC); 1556 Crohn's disease (CD)], 57 had PSC (48 UC-PSC, nine CD-PSC). The prevalence of PSC was higher in UC compared with CD (4.04 vs. 0.58%, P<0.001). We identified the following significant independent risk factors for PSC in patients with UC: male sex [odds ratio (OR) 2.771, P=0.022], pancolitis (OR 2.855, P=0.011), nonsmoker at diagnosis (OR 9.253, P=0.030), and a history of appendicectomy (OR 4.114, P=0.019). During a median follow-up time of 74.8 months, four (7.0%) of PSC patients developed cholangiocarcinoma, six (10.5%) underwent liver transplantation, and five (8.8%) died. Survival of IBD-PSC patients was significantly worse compared with IBD patients without PSC (P=0.001). UC-PSC patients developed significantly more frequently colorectal cancer compared with UC patients without PSC (2/48 vs. 9/1440, P=0.017). Approximately 4% of UC patients and 0.6% of CD patients had PSC. Male sex, pancolitis, nonsmoker status, and a history of appendicectomy were significantly associated with PSC. PSC is associated with considerable morbidity and mortality in the long term.

Inflammatory bowel disease in liver transplanted patients.

Most common hepatobiliary manifestation of inflammatory bowel disease (IBD) are primary sclerosing cholangitis (PSC) and autoimmune hepatitis, ranking them as the main cause of liver transplantation (LT) in IBD setting. Course of pre-existing IBD after LT differs depending on many transplant related factors. Potential risk factors related to IBD deterioration after LT are tacrolimus-based immunosuppressive regimens, active IBD and cessation of 5-aminosalicylates at the time of LT. About 30% patients experience improvement of IBD after LT, while approximately the same percentage of patients worsens. Occurrence of de novo IBD may develop in 14%-30% of patients with PSC. Recommended IBD therapy after LT is equivalent to recommendations to overall IBD patients. Anti-tumor necrosis factor alpha appears to be efficient for refractory IBD. Due to potential side effects it needs to be applied with caution. In average 9% of patients require proctocolectomy due to medically refractory IBD or colorectal carcinoma. The most frequent complication in patients who undergo proctocolectomy with ileal-pouch anal anastomosis is pouchitis. It is still undeterminable if LT adds to risk of developing pouchitis in PSC patients. Annual colonoscopies are recommended as surveillance and precaution of colonic malignancies.

Acute and chronic hepatobiliary manifestations of sickle cell disease: A review.

Sickle cell disease (SCD) is a common hemoglobinopathy which can affect multiple organ systems in the body. Within the digestive tract, the hepatobiliary system is most commonly affected in SCD. The manifestations range from benign hyperbilirubinemia to overt liver failure, with the spectrum of acute clinical presentations often referred to as “sickle cell hepatopathy”. This is an umbrella term referring to liver dysfunction and hyperbilirubinemia due to intrahepatic sickling process during SCD crisis leading to ischemia, sequestration and cholestasis. In this review, we detail the pathophysiology, clinical presentation and biochemical features of various acute and chronic hepatobiliary manifestations of SCD and present and evaluate existing evidence with regards to management of this disease process. We also discuss recent advances and controversies such as the role of liver transplantation in sickle cell hepatopathy and highlight important questions in this field which would require further research. Our aim with this review is to help increase the understanding, aid in early diagnosis and improve management of this important disease process.

Paraneoplastic Manifestations of Lymphoproliferative Neoplasms

Paraneoplastic syndromes, although rare, have been associated with lymphoproliferative disorders. Hodgkin’s lymphoma (HL) is the most common lymphoid neoplasm known to cause paraneoplastic syndromes. These syndromes can often be the earliest manifestation of the underlying malignancy, and treating the underlying lymphoma can cure the paraneoplastic disease. Paraneoplastic diseases reported in lymphoid malignancies can be broadly classified into hematological, neurological, and dermatological syndromes based on the organ systems that are predominantly involved. In addition, renal and hepatobiliary involvement has also been reported. The pathogenesis of the hematological paraneoplastic conditions primarily involves the production of autoantibodies by the neoplastic lymphocytes, which then subsequently leads to cytopenias. Cytoses are a result of cytokine produced by the neoplasms. The administration of corticosteroids along with chemotherapy for the underlying malignancy is the treatment of choice. Neurological paraneoplastic phenomena have been reported in both HL and non-Hodgkin’s lymphoma (NHL). They are thought to be secondary to an immune-related process that is triggered by the underlying process. Both the central and the peripheral nervous systems can be affected. Often, treatment of the underlying malignancy with chemotherapy can result in reversal of the paraneoplastic syndrome. In peripheral neuropathies, muscle relaxants and analgesics are often used for symptomatic relief. Dermatological manifestations, pemphigus vulgaris in particular, often precedes the malignancy. Renal and hepatobiliary manifestations, although rare, are also associated with lymphomas.

Gastrointestinal, Pancreatic, and Hepatobiliary Manifestations of Cystic Fibrosis.

Pulmonary disease is the primary cause of morbidity and mortality in people with cystic fibrosis (CF), but significant involvement within gastrointestinal, pancreatic, and hepatobiliary systems occurs as well. As in the airways, defects in CFTR alter epithelial surface fluid, mucus viscosity, and pH, increasing risk of stasis through the various hollow epithelial-lined structures of the gastrointestinal tract. This exerts secondary influences that are responsible for most gastrointestinal, pancreatic, and hepatobiliary manifestations of CF. Understanding these gastrointestinal morbidities of CF is essential in understanding and treating CF as a multisystem disease process and improving overall patient care.