Angiotensin converting enzyme where is it found in the body

Abstract The renin-angiotensin system RAS plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance. Publication types Research Support, Non-U. Gov't Review. Figure 1. Schematic representation of ACE2 expression in human organs. ACE2 protein expression is present in heart, kidney, testis, lung type I and type II alveolar epithelial cells , nasal, and oral mucosa and nasopharynx basal layer of the non-keratinizing squamous epithelium , smooth muscle cells and endothelium of vessels from stomach, small intestine and colon, in smooth muscle cells of the muscularis mucosae and the muscularis propria, in enterocytes of all parts of the small intestine including the duodenum, jejunum, and ileum but colon , skin basal cell layer of the epidermis extending to the basal cell layer of hair follicles smooth muscle cells surrounding the sebaceous glands, cells of the eccrine glands , endothelial, and smooth muscle cell of the brain There is no question that the ACE2 receptor is also expressed at the level of epithelia of the respiratory system tracheal and bronchial epithelial cells, alveolar epithelial cells, type 2 pneumocytes , cardiovascular system endothelium of coronary arteries, myocites, epicardial adipocites, vascular endothelial, and smooth cells , gastrointestinal tract esophagus keratinocytes, gastrointestinal epithelial cells, intestinal epithelial cells, duodenum, small intestine, rectum , urogenital system kidney proximal tubules, bladder urothelial cells, luminal surface of tubular epithelial cells, testis, seminal vesicle , as well as in the liver and gallbladder and in the nervous system.

Many studies over the years have focused on the role of ACE2 in the cardiovascular system, both for the functions of the renin—angiotensin system RAS system and for the study of new therapeutic targets in cardiac pathologies 15 , ACE2 is recognized as a protector of vascular tissues, balancing angiotensin II effects, protecting endothelia, and promoting mechanisms of regeneration Intuitively, ACE2 impairments leads to severe cardiac dysfunction, with increased atherosclerosis, and endothelial damage.

ACE2 is studied also in hypertension models, as genetic variation affects systolic function in men and ventricular mass in women Not by chance, increased levels of ACE2, both at the gene level and protein expression, but also in circulating soluble forms, are detected after myocardial injury, suggesting a potential role as cardiac biomarker Cardiac alterations result to be usually correlated with thyroid dysfunction, particularly to hyperthyroidism Thyroid hormones also seem to act on ACE2 expression both influencing the receptor gene expression and conditioning the release of ACE from lung endothelium The activity of ACE2 in cardiovascular system is strictly related to those in brain, as ACE2 is expressed in the neuronal area deputy to cardiovascular control, so that is result to be less expressed in case of cardiac injury, while an over-expression in brain leads to a protective action, via reduction of pro-inflammatory cytokines and augmentation of NO activity Many animal models have been used for the study of ACE2 role in the brain.

Data highlighted the antihypertensive and sympatholytic action of ACE2 in the hypothalamus via reduction in Ang II and increase in Ang- 1—7 levels, and a positive effect of ACE2 in the neuronal recovery from stroke ACE2 is also involved in mechanism of memory, via regulation of brain-derived neurotrophic factor expression, and the production of reactive oxygen species, in stress response, regulating corticotropin releasing hormone at hypothalamus level, and in neurogenesis related to serotonin level, secondary to the availability of its precursor tryptophan 39 , The fil rouge between tryptophan synthesis and ACE2 crosses the activity in many systems and binds their functionality.

In fact, ACE2, involved in the RAS mediated homeostasis, plays at intestinal level regulating the microbiome, acting on amino acid uptakes, and expression of antimicrobial peptides ACE2 acts as amino acid transporter, binding B0AT1, a neutral amino acid transporter, in the small intestine, and in animal model of ACE2 deficiency a reduction of tryptophan levels in the blood has been demonstrated This reduction is reflected in the intestine with greater inflammation at the level of the colon, endothelium alteration and reduced ability to damage response, involving also mammalian target of rapamycin mTOR pathway, a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases During the years attention was addressed also to the intestine, since it is known to express the highest level of ACE2 In addition to ACE2 localization in the intestine, ACE2 was found in smooth muscle cells and endothelium of vessels from the stomach, and colon, smooth muscle cells of the muscularis mucosae, and the muscularis propria ACE2 was also copiously present in the enterocytes of all parts of the small intestine including the duodenum, jejunum, and ileum, but not in enterocytes of the colon In addition to the gastrointestinal tract, ACE2 has been found in kidney and in pancreas, with dislocation similar to those of ACE2 that is in kidney apical surface area of the proximal tubules and pancreatic acini and islets As for pancreas, the presence of ACE2 influences islets status via regulation of blood pressure and NO release, as well as acting on tissue fibrosis The role of ACE2 has been widely investigated also for the onset of diabetes, as ACE2 deficiency has been associated with impairment of first-phase insulin secretion and of glucose tolerance 45 — The alteration of RAS system and specifically of ACE2 activity induces an alteration of pancreatic islets, due to unbalance NO production, which in turn influences blood flow, also secondary to glucose availability 45 — The wide expression of ACE2 in kidney is not so surprisingly, considering the pivotal role of RAS system in this organ, in which it regulates the electrolytic equilibrium via reabsorption of sodium and water into the blood, while causing excretion of potassium ACE2 acts balancing the RAS activity, regulating renal homeostasis and it is postulated that its activity is more related to a local control than a systemic regulation of blood pressure Effects of reduced ACE2 are described as promoting proteinuria, in particular albuminuria, glomerular disease and are related to diabetic nephropathy, with lower ACE2 expression at tubular level Despite the role of ACE2 in hepatic glucose metabolism is not completely investigated, the alteration of the ACE2 pathway is, also in this localization, related to the development of impairment of metabolic activity, and in particular of insulin resistance ACE2 in liver has been found expressed in endothelial cells, bile duct cells, and perinuclear hepatocytes and it was mostly elevated in hepatic fibrogenic resistance Notably, insulin resistance correlates with endothelium-dependent and insulin-mediated vasodilatation 46 , In addition, a recent RNA-seq data in the human protein atlas database have shown the highest expression of ACE2 in liver cholangiocytes, followed by hepatocytes ACE2 expression seems to be correlated to the sensory organs.

However, the real expression of ACE2 at ocular level, instead, seems to be still object of debate. Although it is the least widely expressed among the RAS system components, ACE2 is detectable in the aqueous humor 51 , Some papers declare a not significant mRNA presence and immunoreactivity of ACE2 in human conjunctiva 53 , while according to others, ACE2 gene expression is detectable both in human conjunctiva and primary pterygium tissues, even if in a reduced cohort of patient In addition, in the oral and nasal mucosa and in the nasopharynx, ACE2 expression was found in the basal layer of the non-keratinizing squamous epithelium Human ACE2 was detected in ciliated airway epithelial cells of human airway tissues derived from nasal regions Concerning ACE2 presence at the ear level no data were present on human.

However, a recent online study found high expression of ACE2 in the cat ear tip Another sensory organ where ACE2 was also found is at the skin level The activity of RAS system in controlling cell proliferation and differentiation, also in case of tissues injury in the mechanism of self-renewed of damaged cells and neo-angiogenesis, is reflected also in the skin, where the epidermal stem cells express the different players of this system, including ACE2 Immunohistochemical evaluation of ACE2 presence in healthy and oncologic patients showed ACE2 in basal cell layer of normal epidermis and sebaceous glands and a reduction of ACE2 reactivity in patients affected by pre-malignant lesions actinic keratosis and non- melanoma malignant skin cancers basal cell carcinoma and squamous cell carcinoma , suggesting an involvement in the pathogenesis of the disease Considering the role of Angiotensin II in the menstrual cycle, the presence of ACE2 in the female reproductive systems appear quite intuitive.

In fact, AngII acts on follicular, ovulatory and luteinic phases, influencing follicle development, oocytes maturation, and corpus luteum progression, balancing the levels of steroid hormones In addition, it promotes spiral artery vasoconstriction and endometrium regeneration at the uterus level. Angiotensin II has been identified also as a player in endometrium fibrosis and endometrial metastases In parallel, ACE2 expression has been detected also in testis, particularly in spermatogonium and Leydig and Sertoli cells, with possible correlation with spermatogenesis and maintenance of functional and structural integrity of the apparatus Finally, despite the presence of ACE2 in numerous organs, tissues and cells have not been completely clarified and in many of them not yet investigated, ACE2 seems to be absent in the spleen, thymus, lymph nodes, bone marrow, and in several cells of the immune system 15 , In this moment, with the ongoing COVID pandemic, this rapid overview related to the distribution, expression and activities of the ACE2 in human body could help and improve our understanding on potential infection routes of SARS-CoV-2 through the body.

Thus, in the next section we discuss how the presence, distribution and abundance of ACE2 in specific target organs may be related to the COVID clinical symptoms and manifestations.

Most of the studies were guidelines on how to perform nasal and oropharyngeal swab procedure for the screening of COVID infection. The other studies detected, analyzed and discussed the different nasal manifestations in COVID patients Orhinolaryngological symptoms resulted common manifestations of COVID, particularly in mild or moderate form of the disease 65 , The nasal cavity and turbinates have important physiological functions in filtering, warming, and humidifying inhaled air and these functions are critical during SARS-CoV-2 infection since the nasal cavity is the principal gateway for virus entrance.

In fact, epithelial cells in this region are considered suitable clinical sample for early virus detection. Increasing number of reports on SARS-CoV-2 positive patients described olfactory dysfunction, such as loss of smell, cacosmia, phantosmia nasal obstruction or rhinorrhea, and nasal congestion 1 , 67 — 73 1. Some data also reported SARS-CoV-2 positive patients with isolated anosmia, without any other symptoms, suggesting these patients as a potential source of rapid virus spread 68 , 69 , Lechien et al.

Additionally, Kaye et al. However, an Asian study reported a lower percentage of patients with olfactory dysfunctions in comparison to European patients This aspect may be probably due to the diverse ACE2 polymorphisms and expression level between Asian and European individuals The loss of smell in SARS-CoV-2 patients may be caused by different factors, such as localized olfactory cleft oedema, architectural deformity of the olfactory neuroepithelium, or direct neuro-invasion of the olfactory nerve pathways.

However, to date, whether ACE2 expression in the olfactory epithelium is neuronal or non-neuronal or if it occurs in both cell types it is not completely clear 77 , Concerning the non-neuronal expression of ACE2, it could be due to the nasal cavity olfactory epithelium that would work as virus reservoir 79 , Several RNaseq transcriptome reports conducted in human and murine olfactory epithelium suggested a non-neuronal expression of ACE2 as well as of TMPRSS2 79 — 82 , but further studies are mandatory to confirm these finding.

It was also shown that nasal brushing epithelial cells, nasal turbinate epithelial cells, and nasal airway epithelial cells contained ACE2-expressed and TMPRSS2-expressed cell clusters Several studies evaluated the presence of SARS-CoV-2 in saliva through entry into the oral cavity with several potential pathways, via a direct infection of oral mucosa lining cells, via droplets from the respiratory tract, from the blood circulation by gingival crevicular fluid, or via extracellular vesicles released from infected cells and tissues To et al.

Chen et al. Thus, the possible role and function of salivary gland cells in the initial SARS-CoV-2 entry and progress must be further considered and validated as well as their potential function as virus reservoir, able to establish a persistent infection which could last also for months Furthermore, it should be underlined that the saliva samples not only contain saliva secreted from the salivary glands but also the secretions from the nasopharynx and from the lung via the action of cilia lining the airway.

A recent case series presented several cases of SARS-Cov-2 infection where the loss of taste was also associated with oral lesions These lesions presented two distinct patterns, one resembling aphthous-like ulcers in young patients with mild cases of COVID and another with more widespread patterns resembling Herpes Simplex Virus 1 necrotic ulcers in the more severe and immunosuppressed older individuals Whether these lesions were due directly by SARS-CoV-2 or were an associated manifestation resulting from the severe compromised state of the patient remains to be determined.

However, what is known is that taste disorders are linked to an extensive variety of viral infections Upper respiratory tract infection can lead to acute onset ageusia because of viral damage to the olfactory epithelium Furthermore, as previously reported for the nasal cavity, viruses can also use the olfactory nerve as a route into the central nervous system CNS. Thus, ageusia may be a secondary result of olfactory dysfunction. Furthermore, ACE2 positive cells were enriched in epithelial cells, thus damage of mucosal epithelial cells of the oral cavity may explain ageusia, oral mucosal ulcerations, and necrosis detected in SARS-CoV-2 patients 31 , In addition, it was reported that the ACE2 within oral mucosa is also expressed in lymphocytes, and comparable results were also reported for other organs of the digestive system However, since the ACE2-positive lymphocytes is quite few whether this aspect could indicate that SARS-CoV-2 attacks the lymphocytes and leads to the severe disease in patients' needs further studies Currently, the presence and prevalence of ocular manifestations in SARS-CoV-2 infection, consistent with conjunctivitis and including conjunctival hyperemia, chemosis, epiphora, or increased secretions, are still controversial 92 — Wu et al.

In addition to conjunctivitis other ocular abnormalities directly correlated with the COVID severity seem to be alterations in retina and in its vasculature A recent study evaluating the retina of patients with COVID, within 30 days from the onset of systemic symptoms, found an enlargement of retinal arteries and veins in more severe cases and showed an inverse correlation with time to symptoms onset In this context, Casagrande et al. Differently, Xie et al. Despite this point is still debated, it is critical to underline that ocular surfaces have a great tropism for respiratory viruses and also for coronavirus , Based on the current literature, several reports hypothesized that the exposure of the ocular surface to SARS-CoV-2 could lead to infection probably due to the drainage of virus particles via the nasolacrimal duct, specifically through the lacrimal canaliculi that drain tears from the eye surface into the nasal cavity, into the respiratory tract , In this context it is important to emphasized that others reports also considered the presence of ACE2 and TMPRSS2 on the cornea and conjunctiva as a possible virus route 56 , , However, to date, there are no clear evidences that SARS-CoV-2 virus, in humans, can enter inside the eye or spread to the brain through corneal nerves While SARS-CoV-2 was detected in many organ systems, the lungs seems to be the main organs affected by the virus 96 , In fact, it is known that the upper respiratory tract and lungs serve as predominant site of virus entry and replication and that SARS-CoV-2 patients showed the symptoms of pneumonia and alveolar damage The most common and severe complication in patients with SARS-CoV-2 patients is acute hypoxemic respiratory failure or acute respiratory distress syndrome that lead to oxygen and ventilation therapies 1 , — Some of these critically ill patients also required intubation and invasive ventilation.

The most common patterns of radiological images and CT scans were ground-glass opacities, consolidation, centrilobular nodules, architectural distortion, bronchial wall thickening, vascular enlargement, traction bronchiectasis, reticulation, crazy paving pattern, intrathoracic lymph node enlargement, and subpleural bands, that cause pulmonary discomfort and require rapid diagnosis and treatment 1 , — A more widespread histological pattern of alveolar damage with greater fibrotic evolution in the lungs was observed in patients who died after a long period of mechanical ventilation In few cases, an intra-alveolar deposition of neutrophilic granulocytes, probably due to superimposed bacterial infection, was also detected Since the distribution of ACE2 in different organs seems to be notably linked to the clinical symptoms of SARS-CoV-2 infection and since the acute respiratory distress syndrome is a potential deadly complication of SARS-CoV-2, research studying lung complications of ACE2 down-regulation are of key significance in this context.

Several studies on lung injury highlighted that ACE2 receptors down-regulation lead to critical inflammatory lesions in the respiratory tract alveolar wall thickening, edema, infiltrates of inflammatory cells, bleeding which seem to be carried out by angiotensin II , — A key point to remark is that the wide surface of alveolar epithelial cells might explain the vulnerability of lungs to the virus invasion. While ACE2 is expressed in the bronchial epithelium and in type 2 pneumocytes, TMPRSS2 results strongly expressed in the cytoplasm of bronchioles and alveolar epithelial cells Since ACE2 was found to exist on alveolar epithelial cells at approximately similar level as in the whole lung, Sato et al.

These data explain why chest CT revealed consolidation and ground glass opacities in the bilateral peripheral lobes in COVID cases However, these factors would not even prevent the simultaneous role of other mechanisms including an altered immune response to initial viral invasion, or a genetic susceptibility to hyper-inflammation and thrombosis 8 , In SARS-CoV-2 pneumonia, thrombosis may play a direct, and critical role in gas exchange abnormalities and in multisystem organ dysfunction.

Unfortunately, to date, as for all the other organs affected by SARS-CoV-2, the lungs impairment during this new infection remain to be further clarified. In most of these reports cardiovascular complications emerged among the most significant manifestations in SARS-CoV-2 infection — Different cardiovascular complications, such as myocarditis, acute coronary syndrome, decompensated heart failure, pulmonary embolism, cardiogenic shock, and infection of a heart transplant recipient, accompanied by altered levels of creatine kinase isoenzyme-MB, myohemoglobin, cardiac troponin I, and N-terminal pro-brain natriuretic peptide were currently reported 1 , — In addition, a high prevalence of pre-existing cardiovascular morbidities, including hypertension, and coronary artery diseases, has been detected among patients with severe SARS-CoV-2 1 , , In COVID patients, the highest mortality rates were also observed in case of pre-existing cardiovascular disease and elevated cardiac troponin levels , Furthermore, patients with higher troponin levels had also increased markers of inflammation, including C-reactive protein, interleukin IL -6, ferritin, lactate dehydrogenase LDH , high neutrophil count, and high amino-terminal pro-B—type natriuretic peptide These mechanisms would involve several factors such as a direct viral damage and an immune-mediated damage by inflammatory cytokines i.

As reported in the previous section, the cardiac tissue presents a high ACE2 expression level This speculation is supported by the occurrence of high level of Furin in the peripheral blood of COVID patients Kuba et al.

This infection can lead to a localized inflammatory response with resulting myocarditis that bring to acute cardiac injury and the prospective for arrythmias or heart failure Autoptic data on SARS-CoV-2 positive patients showed the existence of mononuclear inflammatory myocardial infiltrate, thus supporting this hypothesis also for this new coronavirus 3.

This altered immunologic status has been related with an increased risk of cardiovascular disease and could be also an indirect mechanism of immunological dysfunction that lead to cardiac sequelae — In addition, numerous SARS-CoV-2 positive patients showed respiratory distress that lead to hypoxemia that could cause cardiac injury secondary to an oxygen mismatch — Other systemic consequences of cardiac injury in SARS-CoV-2 patients could also be related to sepsis and disseminated intravascular coagulation DIC that vary from minimal change to interstitial inflammatory infiltration and myocyte necrosis vasculature microthrombosis and vascular inflammation — The kidney is one of the major organs which play a key role in the filters which excrete toxins, waste products, and extra water from our body.

Despite most of the work were focused on kidney transplantation and on the management of dialysis patients during SARS-CoV-2 infection, several studies reported an increased incidence of acute renal injury during the infection , The bladder may also be affected and may ultimately lead to multiple-organ failure and death , Although initial reports suggested that the burden of acute kidney injury during SARS-CoV-2 infection was moderately low about 0.

Several studies also showed that patients with acute renal injury have a higher mortality rate compared to other patients and this is particularly true for those in the ICU — Patients with acute renal injury also showed elevated levels of serum creatinine and blood urea nitrogen associated to higher leukocyte count and lower lymphocyte and platelet counts Prolonged activated partial thromboplastin time and higher D-dimer, both coagulation parameters, were also more common in these patients In addition, a high percentage of SARS-CoV-2 patients with acute renal injury had proteinuria albuminuria and hematuria, along with isolation of viral RNA from urine, all factors that support the potential viral tropism for the kidney , This tropism was also confirmed from an autopsy study by Su et al.

This study also showed the presence of a diffuse proximal tubule injury with the loss of brush border, non-isometric vacuolar degeneration, necrosis, and occasionally hemosiderin granules and pigmented casts In addition, a prominent erythrocyte aggregates obstructing the lumen of capillaries without platelet or fibrinoid material were also detected Clusters of coronavirus-like particles with distinctive spikes in the tubular epithelium and podocytes were also detected.

Post-mortem examination of the viral nucleocapsid protein in situ in the kidney also showed that SARS-CoV-2 antigens is accumulated in kidney tubules, suggesting that SARS-CoV-2 may infects kidney directly, leading to acute renal injury and potentially contributing to viral spread — It was found that both proximal tubular cells or tubular progenitor cells in the kidney co-expressed ACE2 and TMPRSS2 and their expression levels resulted high in nephron epithelial cells, epithelial cells, endothelial cells, and mesangial cells of the kidney 82 , Additionally, Pan et al.

These cells are particularly vulnerable to viral infection and their injury easily induces heavy proteinuria that was detected in about However, kidney disease involvement in SARS-CoV-2 patients is likely to be multifactorial and may be also due to cytokine damage high levels of IL-6 , organ crosstalk Lung-kidney and other systemic effects , A lot of studies showed that the gastrointestinal tract represents a common target organ of SARS-CoV-2 infection 1 , 2 , 29 , 96 , — , — Anorexia appears to be the most common gastrointestinal symptom However, this symptom can be due to gustatory dysfunction, which was found in a high percentage of COVID patients Several data reported that these gastrointestinal manifestations during SARS-CoV-2 infection can be associated with a poor disease course; comparing patients with non-severe disease with those with severe infection it was shown a higher risk of developing gastrointestinal symptoms in patient with severe infection 29 , The occurrence of these gastrointestinal symptoms can not only coexist with other symptoms, but also precedes the typical phenotype of SARS-CoV-2 infection It was shown that also pediatric patients and children with SARS-CoV-2 infection may present digestive symptoms, most commonly diarrhea, in the absence of respiratory symptomatology , Although different clinical features, such as milder disease course symptoms are present in pediatric patients and children with SARS-CoV-2, the gastrointestinal symptoms appear to be similar to those found in adult individuals Despite gastrointestinal symptoms were frequently observed in SARS-CoV-2 patients, to date, the exact significance of these manifestations are still unclear.

An autopsy report, with details of gastrointestinal pathology in a SARS-CoV-2 patient, showed the presence of segmental dilatation and stenosis in the small intestine To date, autopsy data and reports with a full description of the gastrointestinal appearance associated to SARS-CoV-2 infection are still few to allow a clear conclusion.

In addition to the clinical symptoms induced by the gastrointestinal disorders during SARS-CoV-2 infection, these manifestations can highlight one more route of virus transmission, i. An increasing number of data showed that stool samples contain high concentration of SARS-CoV-2 RNA during infection for a relatively long period of time from 1 to 12 days , , This hypothesis is partially confirmed by Lin et al.

Although, there are numerous data on gastrointestinal symptoms during SARS-CoV-2, the exact mechanism by which the virus affects the gastrointestinal tract is still not so clear. The occurrence of several mechanisms has been hypothesized. One mechanism may involve the presence of ACE2 receptors in the gastrointestinal tract. Liang et al. In addition, Zhang et al. In addition, Guo et al. However, a second mechanism could involve a direct injury of the gastrointestinal system due to an inflammatory response cytokine storm Absorptive enterocytes may be infected and destroyed by the virus, probably leading to malabsorption, disturbed intestinal secretion, and an activated enteric nervous system ensuing symptoms like diarrhea Several data reported that approximately half of SARS-CoV-2 patients show liver biochemistry abnormalities, with increased levels of aminotransferases, gamma-glutamyl transferase, bilirubin, and alkaline phosphatase , — Median aspartate aminotransferase-dominant aminotransferase increase seems to indicate the disease severity and seems to be an index of hepatic injury Concerning hepatic injury, Bloom et al.

In addition, it was reported that liver abnormalities seem to be more common in patients with severe disease upon presentation In fact, a recent meta-analysis including 20 retrospective studies with 3, COVID patients revealed that higher levels of alanine aminotransferase, aspartate aminotransferase and bilirubin were associated with a significant increase in the severity of COVID infection A recent meta-analysis also linked elevated admission levels of these markers to patient mortality Other common factors linked with liver injury were decreased lymphocyte count, increase neutrophil count, and male gender However, to date, the exact changes that lead to the altered liver biochemistries in SARS-CoV-2 patients remains unclear.

Post-mortem liver biopsy showed the presence of a moderate microvascular steatosis and a mild lobular and portal activity Another study suggested collateral liver damage from viral-induced cytotoxic T-cells Additionally, since also abnormal coagulation markers have been reported in SARS-CoV-2 patients it is possible that the presence of microthrombi lead to an altered hepatic perfusion and consequent hepatocyte injury and aspartate aminotransferase increase , , Whether these changes can be due to direct viral cytopathic effect, to cytokine release linked with SARS-CoV-2, to ischemia, to a preexisting condition, or to other causes, such as drug-induced liver injury, are currently unknown, also because studies on mechanisms of SARS-CoV-2 related liver dysfunction are limited.

What we know currently is that ACE2 receptor are highly expressed in cholangiocytes However, Zhou et al. In fact, it was shown that alkaline phosphatase, an index of cholangiocytes injury, was the liver parameter less subject to significant alterations during SARS-CoV-2 infection while, aminotransferases and gamma-glutamyl transferase, indicators of hepatocyte injury, were the more common and almost always altered liver parameters in severe SARS-CoV-2 patients As just described, liver injury in COVID may be the direct insult to the liver or bile cells via receptors of ACE2 but it is further aided by hyper-inflammation, cytokine storm or bystander hepatitis and drug-induced damage.

To date the exact mechanism of viral-associated liver injury needs further investigation. Despite few articles were found on gallbladder during SARS-CoV-2 infection, several information on its alteration during the new viremia were found in manuscripts on liver injury , Gallbladder is a storage pouch for bile that is continually produced by liver, thus their functions are strictly related.

Cholestasis in these patients seem to be not associated with age, gender, ICU admission, or gastrointestinal symptoms at presentation The fatality rate seems to be higher among patients with cholestasis than those without cholestasis As for liver, the gallbladder was found susceptible to the infection probably due to the high ratio of gallbladder epithelium cells expressing ACE2 Also in this case the mechanism of viral-associated gallbladder alterations is unclear, although it is obvious that its alterations during SARS-CoV-2 infection are associated with liver injury.

Several of these patients also presented abnormal blood glucose, suggesting that the pancreatic injury might be due directly to cytopathic effect by local SARS-CoV-2 replication 5 , — Additionally, pancreatic injury might be caused indirectly by systemic responses to respiratory failure or to the harmful immune response induced by SARS-CoV-2, which led also to the damage in multiple organs 5.

Similar results were also found by Liu et al. Hadi et al. Specifically, a retrospective analysis by Mao et al. Several case-series and two retrospective studies also reported critical stroke conditions related to COVID , In this context, Beyrouti et al.

Moriguchi et al. These neurological manifestations in the brain of SARS-CoV-2 infected patients were confirmed and recognized by CT scan images and magnetic resonance imaging MRI scan, where presence of necrotizing hemorrhagic encephalopathy, brain thrombosis and acute infarction, eptomeningeal enhancement, perfusion abnormalities, and cerebral ischemic stroke, demyelinating lesions, right temporal lobe edema, and brainstem inflammation, were recognized — In addition, the presence of SARS-CoV2 was identified in frontal lobe tissue by using transmission electron microscopy and by genome sequencing in cerebrospinal fluid of SARS-CoV-2 patients, supporting that this new pneumonia virus can cause nervous system damage These symptoms may be a manifestation of direct CNS invasion, induction of CNS inflammatory mediators but may be also a secondary effect of other organ system failure, an effect of sedative strategies, a prolonged mechanical ventilation time, or environmental factors, including social isolation Despite these data clearly highlighted the involvement of the brain in SARS-CoV-2 infection, the exact mechanism for virus neurotoxicity is not yet straightforward, since this depend on the brain entry route of the virus, which, to date, has not been fully elucidated The pathway of the virus into the brain could be primarily linked to the route of transmission and distribution of intracellular receptors of SARS-CoV Mao et al.

COVID can potentially damage the capillary endothelium within the brain and contribute to elevated blood pressure. However, although ACE2 and TMPRSS2 are present in the nervous system, additional pathways were also hypothesized for the entry of SARS-CoV-2 into the nervous system, including the direct intranasal entry to the brain via olfactory nerves, the indirect entry to the brain go through the blood-brain barrier via hematogenous or lymphatic spread, the hypoxic injury, and finally the immune-related injury 7 , It is known, that coronaviruses can enter to the nervous system straight through the olfactory nerve, potentially causing loss of smell and taste, and enter the nervous system through blood circulation and neuronal pathways.

In addition, coronaviruses, including SARS-CoV-2, trigger harmful effects in the lung tissue leading to several lung lesions and consequent hypoxia, that can be responsible of the brain disease progression. These data highlighted that awareness, management and timely analysis of infection-related neurological complications of SARS-CoV-2 patients are key to improve the prognosis of severe ill patients. Skin manifestations due to SARS-CoV-2 infection are of different types and currently reported in numerous case reports, case series, and literature reviews — The first case study on skin manifestations was published by Recalcati et al.

Subsequently, other authors described urticarial rash petechial also in association with decrease platelet count and sometimes also with eosinophilia — Zhang et al.

In addition to urticarial skin manifestations, Manalo et al. Other described skin manifestations are related to acral ischemia often related to an hypercoagulation status of SARS-CoV-2 patients, that have a negative prognostic implication in virus evolution — Case series showed purpuric skin involvement in severe SARS-CoV-2 patients, in detail retiform purpura on the buttocks, dusky purpuric patches on the palms and soles, and livedo reticularis on the chest and limbs were detected , , Tissue biopsies from skin and lung detected thrombogenic vasculopathy and deposits of C5b-9 and C4d complement proteins This was in line with widespread activation of both alternative and lectin pathways of complement, suggesting that severe SARS-CoV-2 patients can suffer thrombotic microvascular injuries that can involve not only the lungs but also the skin, and probably other organs Skin manifestations were found also in pediatric patient where the skin lesions commonly happen in asymptomatic or mildly symptomatic children and adolescents — Skin biopsy of acral perniosis lesion in SARS-CoV-2 pediatric patients revealed a superficial and deep lymphocytic infiltrate, where vacuolar change and purpura were also present , Hemorrhagic parakeratosis in the stratum corneum were also detected and as well as dermal infiltrate strongly perivascular and perieccrine and lymphocytic vasculitis in the thin muscular walls of small vessels 4 , Similar results were also found in skin biopsies from SARS-CoV-2 adult patients that showed a lymphocytic perivascular and perieccrine infiltrate , To date, there are still not enough studies to define which are the skin manifestations of SARS-CoV-2 infection, and why they occur.

As reported by Recalcati et al. It is an enzyme that generates small proteins — by cutting up the larger protein angiotensinogen — that then go on to regulate functions in the cell. ACE2 is present in many cell types and tissues including the lungs, heart, blood vessels, kidneys, liver and gastrointestinal tract.

It is present in epithelial cells, which line certain tissues and create protective barriers. The exchange of oxygen and carbon dioxide between the lungs and blood vessels occurs across this epithelial lining in the lung. ACE2 is present in epithelium in the nose, mouth and lungs. In the lungs, ACE2 is highly abundant on type 2 pneumocytes, an important cell type present in chambers within the lung called alveoli, where oxygen is absorbed and waste carbon dioxide is released.

ACE2 is a vital element in a biochemical pathway that is critical to regulating processes such as blood pressure, wound healing and inflammation, called the renin-angiotensin-aldosterone system RAAS pathway.

ACE2 helps modulate the many activities of a protein called angiotensin II ANG II that increases blood pressure and inflammation, increasing damage to blood vessel linings and various types of tissue injury. ACE2 is present in all people but the quantity can vary among individuals and in different tissues and cells. Some evidence suggests that ACE2 may be higher in patients with hypertension, diabetes and coronary heart disease.

Studies have found that a lack of ACE2 in mice is associated with severe tissue injury in the heart, lungs and other tissue types. This is unclear.