#Congestive hepatopathy

[mcatmemoranda]

Congestive hepatopathy occurs due to right heart failure--the right atrium and vena cava have high pressure and blood backs up into the central veins of the liver.

It's important to understand the structure of the liver. The hepatocytes are organized into lobules, with a central vein in the middle and 6 portal triads outlining the hexagonal borders of the lobule. Portal triads are made of portal vein, hepatic artery, and bile ducts. Zone 1 is closes to the portal triad. Zone 2 is further from the portal triad, and zone 3 is furthest from the portal triad, but closes to the central vein.

So in congestive hepatopathy, the hepatocytes that are in zone 3, closest to the central veins, are the ones that sustain the most damage. Because of the increased hydrostatic pressure in central veins, fluid leaks out of the central veins and the hepatocytes around the central vein become necrotic. The hepatocytes around the central veins become necrotic, causing centrilobular necrosis. There's a very good picture of this in the UWorld question I'm looking at, but I can't post the image because of copyright stuff. It makes sense to me now why it's called "centrilobular necrosis--" it's literally because hepatocytes in the center of the lobule are necrotic. The hepatocytes around the portal triads in zone 1 are normal because they're farther away from the central vein. Because of the normal appearance of periportal hepatocytes contrasted with the necrosis of the centrilobular hepatocytes, it appears as "nutmeg liver."

[irispublisherscardiovascular]

Aerobic Exercise and S-Klotho Effects on Cardiovascular Disease Patients: A Review

Abstract

Coronary artery disease (CAD) is the most common type of heart disease progression once major coronary arteries are injured or diseased. When the primary blood arteries which supply the myocardium with blood, oxygen and nutrients is narrowed arterial disease progresses. Plaque buildup in the walls of the arteries from hypercholesterolemia (high blood cholesterol), dyslipidemia, and vascular inflammation contribute to atherosclerosis formation, a primary agent for CAD. Arterial stiffens occurs as a result of the biological aging process and arteriosclerosis. Endothelial dysfunction is characterized by reduced vascular nitric oxide levels. Nitric oxide vascular reductions leads to irregularities in blood artery function. These functional irregularities result from atherosclerosis, causing vasoconstriction of small arteries. Vasoconstriction of smaller arteries is related to hypertension and could possibly influence, left ventricle diastolic dysfunction. There are two forms of klotho; membrane and secreted, membrane klotho acts as co-receptor for fibroblast growth factor (FGF)-23, while secreted klotho (s-klotho) regulates nitric oxide production in the endothelium minimizing endothelial dysfunction. Studies examining the effect of aerobic exercise on blood circulating s-Klotho have demonstrated a fitness dependent response. S-Klotho values have been shown to be significantly higher in trained vs untrained individuals. Aerobic training is an appropriate model for mechanistically probing the role of physical activity on s-Klotho expression. Factors associated with endothelial function improvement; aerobic fitness levels and aerobic training increased s-klotho levels alleviate and attenuate endothelial dysfunction. Aerobic exercise and klotho gene expression is shown to reduce cardiovascular events in patients with prior CAD thereby decreasing mortality risk.

Read More About This Article: https://irispublishers.com/ojcrr/fulltext/aerobic-exercise-and-s-klotho-effects-on-cardiovascular-disease-patients-a-review.ID.000619.php

Read More Iris Publishers Google Scholar Article: https://scholar.google.com/citations?view_op=view_citation&hl=en&user=LxGGn5cAAAAJ&cstart=20&pagesize=80&citation_for_view=LxGGn5cAAAAJ:epqYDVWIO7EC

[shadingadream]

Congestive hepatopathy aka “nutmeg liver”

Right-sided heart failure results in the backup of blood through the hepatic vein and into the liver, resulting in severe hepatic congestion. The pooling of blood causes the surface of the liver to take on a “nutmeg” appearance.

[iqr2com]

ما هو احتقان الكبد - موقع اقرا

ما هو احتقان الكبد – موقع اقرا

احتقان الكبد يُعرف احتقان الكبد أو تضخم الكبد الاحتقاني (بالإنجليزية: Congestive hepatopathy) بأنّه اختلال يُصيب الكبد نتيجة اضطرابات القلب والأوعية الدموية، خاصةً في حالات قصور الجانب الأيمن من القلب، الذي يترتب عليه حدوث احتقانٍ مزمنٍ في الكبد، وقد يؤدي ذلك في المراحل المتقدمة من المرض إلى تليّف الكبد (بالإنجليزية: Hepatic fibrosis)، ومن الجدير بالذكر أنّه يُطلق على هذه الحالة تليف أو تشمع…

[imagecase]

A 26-year-old male with no significant past medical history presented with five days of fever and chest pain. He was found to have Methicillin-Sensitive Staph Aureus (MSSA) bacteremia and aortic valve infective endocarditis with an aortic root abscess. Echocardiogram revealed moderate to severe aortic insufficiency and a Ventricular Septal Defect (VSD). He was taken to surgery for repair of this VSD. During surgery, the VSD was found to be communicating from the Left Ventricular Outflow Tract (LVOT) to the Right Atrium (RA). This rare occurrence of left-to-right shunt from LV to RA is known as the gerbode defect. He underwent successful surgical repair of VSD with an autologous pericardial patch along with debridement and reconstruction of aortic annulus as well as aortic root replacement. The VSD was closed with an autologous pericardial patch. Ten days later, the patient was readmitted to the hospital with shortness of breath and a “pounding” sensation in his heart as well as in his neck. Transesophageal echocardiogram showed worsening of the gerbode defect with dehiscence of the pericardial patch. Video 1 shows a unilateral pulsating right jugular vein. Pulsation is not as prominent on the left side as it is on the right side. These pulsations are reflective of the left ventricular pressure that is directly transmitted to the right atrium via the shunt and up into the right jugular vein.

The patient also developed Right Upper Quadrant (RUQ) pain that was thought to be due to liver engorgement from severe left-to-right shunt. Video 2 shows a pulsating liver. Upon closer inspection, it will be noted that the black object taped to the RUQ has a pulsating motion. The motion is more appreciable upon palpation than on visual assessment. We did our best to capture this rare physical exam finding by using an object. This liver engorgement and pulsation is reflective of congestive hepatopathy from right heart failure caused by severe left-to-right shunt.

The young man underwent a second successful repair of the gerbode defect. This time, with a bovine pericardial patch along with aortic valve and root replacement. Post operatively, these physical exam findings had resolved.

[crimsonpublisherssurgery]

For the Right Hemiliver Graft May Need Tissue Expander After Living Donor Liver Transplantation

For the Right Hemiliver Graft May Need Tissue Expander After Living Donor Liver Transplantation by Batsaikhan B in Surgical Medicine Open Access Journal

Introduction: Hepatic venous outflow is an important for the graft survival in living donor liver transplantation. Hepatic venous outflow obstruction generates liver failure, which may influenced due to graft malposition, which unsized upper part of abdomen between donor and recipient. The number of Liver Transplantation (LT) increases last few years, which is related with populating the high surgical technology in developing country like in Mongolia. The main reason of LT is a hepatitis B virus-related liver cirrhosis in Mongolia. Liver transplantation had started since 2011 under the supporting of Professor Sung Gyu Lee from hepato-biliary surgery and liver transplantation of ASAN Medical Center. Veno-Occlusive Disease (VOD), Budd-Chiari Syndrome (BCS), and Congestive Hepatopathy (CH), all of which results in hepatic venous outflow obstruction. The early Hepatic Venous Outflow Obstruction (HVOO) is a rare, however that could raise a serious complication as a graft failure and eventual lose. We report a case of early HVOO, which may result of size mismatch of abdominal cavity. The size mismatch of abdominal cavity may produce kinking syndrome after transplantation of right lobe, which reveals the HVOO without anastomosis complication. Methods: A 38-year-old male patient with liver cirrhosis due to HBV, HDV, HCC in S8 of the liver (CTP-B, MELD-18). On the first postoperative day the patient developed impairment of the liver function. Doppler ultrasound (US) showed the different speed of RHV preanastomosis and postanastomosis field. This was diagnosed acute liver failure due to veno-oclusive disease, after that started intensive therapy

https://crimsonpublishers.com/smoaj/pdf/SMOAJ.000584.pdf

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[pushmycartpmc]

DR. Reckeweg R7 Liver and Gall bladder drops

Organic and functional complaints of liver and gallbladder, hepatopathy, cholecystophathy, calculi, disturbances of the biliary secretion, hepatitis, swelling of the abdomen, premature satiety, lack of appetite, bitter taste in mouth, flatulence, constipation, weariness after meals, irritation, hypochondria.

MODE OF ACTION OF MAIN INGREDIENTS: Carduus marianus: Painful swelling of the liver, jaundice, biliary calculi, cholangitis.

Chelidonium: Swelling of the liver with sensation of pressure on licer and biliary vesicle and extending to right shoulderblade, cholagogue.

Cholesterinum: Enlargement of the liver, jaundice and formation of gallstones.

Colocynthis: Cramplike pains in abdomen, cannot stand pressure of clothes. At the time a pain occurs, improvement is obtained through strong pressure on abdomen and through bending over. Lycopodium: Meteorism and flatulence, bitter taste in mouth, bad humour, constipation. Nux vomica: Hypochondria, liver constriction and congestion, nausea, abuse of tobacco, icterus, gastro-duodenal catarrh, constipation. Buy DR. RECKEWEG R7 Liver and Gall bladder drops online from pushmycart.com.

BENEFITS 

 It is beneficial in ailments of hepatopathy, cholecystography, calculi disturbances, hepatitis, swelling of the abdomen.

 It helps to counter flatulence, constipation, lack of appetite.

 It helps to overcome fatigue, hypochondria.

 It is useful in dealing with problems of liver and gall bladder.

DOSAGE - Generally 3 times a day 10-15 drops in some water before meals. - If no improvement occurs within 8-14 days take 10-15 drops 4-6 times a day and reduce the dose when improving. Even after complete disappearance of the complaints, take 10-15 drops - 1-3 times a day for a longer period of time, watching diet rigorously. Use under medical supervision.

[medicowesome]

Congestive hepatopathy

http://dlvr.it/RQqPlB

[irispublisherscardiovascular]

Aerobic Exercise and S-Klotho Effects on Cardiovascular Disease Patients: A Review

Authored by TJ Exford*

Abstract

Coronary artery disease (CAD) is the most common type of heart disease progression once major coronary arteries are injured or diseased. When the primary blood arteries which supply the myocardium with blood, oxygen and nutrients is narrowed arterial disease progresses. Plaque buildup in the walls of the arteries from hypercholesterolemia (high blood cholesterol), dyslipidemia, and vascular inflammation contribute to atherosclerosis formation, a primary agent for CAD. Arterial stiffens occurs as a result of the biological aging process and arteriosclerosis. Endothelial dysfunction is characterized by reduced vascular nitric oxide levels. Nitric oxide vascular reductions leads to irregularities in blood artery function. These functional irregularities result from atherosclerosis, causing vasoconstriction of small arteries. Vasoconstriction of smaller arteries is related to hypertension and could possibly influence, left ventricle diastolic dysfunction. There are two forms of klotho; membrane and secreted, membrane klotho acts as co-receptor for fibroblast growth factor (FGF)-23, while secreted klotho (s-klotho) regulates nitric oxide production in the endothelium minimizing endothelial dysfunction. Studies examining the effect of aerobic exercise on blood circulating s-Klotho have demonstrated a fitness dependent response. S-Klotho values have been shown to be significantly higher in trained vs untrained individuals. Aerobic training is an appropriate model for mechanistically probing the role of physical activity on s-Klotho expression. Factors associated with endothelial function improvement; aerobic fitness levels and aerobic training increased s-klotho levels alleviate and attenuate endothelial dysfunction. Aerobic exercise and klotho gene expression is shown to reduce cardiovascular events in patients with prior CAD thereby decreasing mortality risk.

Keywords:Atherosclerosis; Nitric oxide; Reactive oxygen species (ROS); Endothelial dysfunction; Klotho; Coronary artery disease; Oxidative stress

Introduction

Cardiovascular diseases are prevalent in the general population and are the leading cause of death worldwide responsible for 46.2% of noncommunicable deaths [1,2]. Coronary artery disease (CAD) broadly comprises CAD myocardial infarction, vascular stiffening, and left ventricular hypertrophy [3]. CAD regularly advances over long periods and is the most common type of heart disease that progresses once major coronary arteries are injured or diseased. Arterial diseases progress once the main blood arteries that supply the myocardium and the different organs with blood, oxygen, and nutrients is narrowed. Inflammation and cholesterol that creates plaque in the arteries are the cause for arterial diseases [4]. Plaque buildup in the walls of the arteries from hypercholesterolemia, fatty deposits, other substances and inflammatory mechanisms combine dyslipidemia to atheroma development, are usually the main causes for CAD [5]. Once plaque is present, decrement in blood flow to the body’s organs occur which in turn, decrease blood flow causing reduction in oxygen delivery to the tissues and thus, ischemia [6]. The additional arterial tension and subsequent damage due to hypertension cause the coronary arteries to become narrowed from accumulation of fat, cholesterol and other molecules that collectively is the slow process of chronic inflammatory disease [7].

Atherogenesis is the process of forming plaques in the intima layer of arteries. Plaque’s compositions include mainly fat, cholesterol, and calcium [8]. With time, arterial diameter narrows decreasing arterial blood flow. This progression is termed atherosclerosis. Thus, atherogenesis is a multifaceted interface of risk factors with cells of the artery wall, the blood, and molecular communications [9]. Initial atherosclerosis is the consequence of the endothelial cells in the intima layer capturing monocytes along with endothelial permeability aiding the low-density lipoprotein elements to drift into the arterial wall. Myocytes develop and become macrophages that consume the low-density lipoprotein units with apolipoprotein apoB molecule to form foam cells. Oxidative radicals oxidize the apoB molecule, assemble the units mainly designated to be phagocytized by macrophages [10].

Damage progression is the second stage where the migration of the smooth muscle cells from the arterial wall intima layer into the tunica intima. The next stage is the formation of thrombosis. The rupture of the thin cap fibroatheroma that covers the plaque plus the coagulation components of blood interact with the thrombogenic plaque produces thrombi [11]. In addition, risk factors such as, high cholesterol values, hypertension, diabetes, overweight and oxidative radicals affect the early phase of atherogenesis, namely endothelial dysfunction [12,13]. In brief, atherosclerosis develops progressively with inflammation and lipid accumulation. Atherogenesis is the course of creating plaques in the intima coating of arteries. The buildup of lowdensity lipoprotein and the inflammation of the arterial wall are the first phase of atherosclerosis. Atherogenesis results from lipid peroxidation‐derived aldehydes oxidized to carboxylic acids. The pro-inflammatory oxidized phospholipids, resulting of the oxidation of low-density lipoprotein and phospholipids including arachidonic acid, formed in the lipoxygenase and myeloperoxidase pathways, these molecules attract and trigger inflammatory cells, such as monocytes, T-cells, and macrophages. Matrix degradation brings about atherosclerotic as a result of macrophages activation through; cytokines, reactive oxygen species (ROS), and proteolytic enzymes. Oxidative stress is also considered to be a key factor in mechanisms of changes in cell function [14], such as the aging process [15].

Klotho is an anti-aging gene with implications in biological and anatomical processes, mainly in cardiovascular disease [16]. Early human aging involving endothelial dysfunction, vascular calcification and progressive atherosclerosis were seen in mice lacking Klotho [17]. In addition, reduced Klotho levels is observed in coronary artery disease patients, physically inactive individuals and in aging. S-Klotho has a role in the action of fibroblast growth factor 23 (FGF23), which directly binds to FGF receptors (FGFRs). This, high affinity complex for FGF23 mediates the intracellular effects of metabolism of phosphorus as the required co-receptor [18]. Other mechanisms which s-klotho is involved, include reserve oxidative stress, inflection of inflammation or attenuation of vascular stiffening [19,20]. Therefore, Klotho has been suggested as a master regulator of cardiovascular disease [21].

Aerobic exercise and Klotho gene expression could reduce the risk of cardiovascular events in patients with prior coronary artery disease thus, aerobic exercise may decrease the risk of mortality, incidence and severity of cardiac events [12,15, 22-24]. In addition, in patients with CAD exercise training improves endotheliumdependent vasodilatation both in epicardial coronary vessels and in resistance vessels [24) Patients with significant coronary artery disease present lower soluble concentrations of α-Klotho (s-Klotho) [25], as well as reduced levels of Klotho gene expression in the vascular wall [26]. This protein is related to the attenuation of vascular calcification as well as prevention of cardiac hypertrophy [27]. Reduced serum s-Klotho concentrations and decreased vascular Klotho gene expression were associated with the presence as well as the severity of coronary artery disease independently of other established cardiovascular risk factors [14,23]. S-Klotho is a pleiotropic protein related to longevity, which acts as a co-receptor of the fibroblast growth factor 23 and has been proposed as a key regulator of the development of cardiovascular disease. In the few published clinical studies, an association between low levels of s-Klotho and the occurrence and severity of cardiovascular disease have been reported, as well as a reduction of cardiovascular risk when levels were high [28].

Arterial Endothelial Dysfunction

Arterial endothelium assists vasomotor tone and function by producing and discharging nitric oxide [29]. Arterial endothelium is characterized by cells in the inner layer of all blood arteries and lymphatic system. The inner layer of arteries and veins is the tunica Intima. In arteries, this layer is composed of an elastic membrane lining and smooth endothelium which is a unusual type of epithelial tissue that is covered by elastic tissues. The small thickness of endothelium at the capillaries level permits molecules movements actively and passively as well as ions among blood and lymph by means of the tissues [30]. Following the endothelial layer, elastic fibers thickness varies, which is in a straight line associated to its ability to change vessels’ blood volume, pressure and flow velocity [31]. Arterial endothelium contributes to the regulation of blood coagulation, platelet and leukocyte action, vessel’s tone and inflammatory responses [32]. The endothelium plays an important role in blood vessel functions by producing various signaling molecules [33]. It is a vital regulator of blood flow and blood pressure in the circulatory system. The endothelium is the internal coating of cells that has several critical functions, it controls the correct vessels’ radius namely; constriction or dilation, thus changing rapidly blood’s amount delivered to the various organs. The endothelium also protects the tissues from various toxic substances by: a. coagulation or formation of a fibrin clot, which is a mechanism that blood changes from a liquid to a gel, it includes activation, bond, and accumulation of platelets along with deposition and maturation of fibrin, b. controls the fluid, c. regulates electrolytes’ levels and, d. exchange of numerous substances between the blood and the tissues and Vic versa, and, e. regulates inflammation damages in the tissues. Consequently, Endothelium function is critical for the regular function of the arteries, tissues and organs [34].

Existence of hypertension and dyslipidemia are directly associated to endothelial dysfunction resulting inflammatory and arterial damage [35]. The coronary artery response to acetylcholine rest on the capacity of the endothelium and the endothelial nitric oxide pathway [36]. Arteriosclerosis affects the major elastic and muscular arteries in the extracellular intermediate of arteries elasticity resulting in arterial stiffens [37]. Arterial stiffens outcomes after a deteriorating course affecting mostly the extracellular medium of elastic arteries. It expresses the arterial wall viscoelastic capacity which affects arterial smooth muscle and therefore, the regulation of blood flow, blood pressure, arterial pulse, permeability, and inflammation [38,39]. Changes in extracellular medium proteins and mechanical properties of the arterial wall associated to vessel stiffening can trigger other mechanisms implicated in the progress of atherosclerosis. With time, arterial stiffness increases progressively, exposing the individuals to a greater pressure variation related to increased risk of stroke and renal impairment [40]. Changes in arterial pulsatile lead to an increase in the slow frictional force of blood flow counter to the vessel wall [41]. However, increased wall shear stress reduces nitric oxide production by the endothelial that in turn, increases rate of atheromasias (artery inflammatory) development [42,43]. During aerobic exercise training, systolic blood pressure increases thus, pressure in the artery wall rise resulting in the activation of the autoregulation mechanism and thus, vasodilation, that in turn, improves blood flow [44] and thus, has the potential to minimize these pathological process’ and to reduce the amount of cardiovascular complications [35].

Dysregulation of the nitric oxide normal smooth muscle contraction properties response is usually characterized by endothelial dysfunction, following advanced atherosclerosis and increase oxidative stress [45]. that induces endothelial dysfunction and atherosclerosis progression by reducing nitric oxide availability [46]. Endothelial dysfunction is a significant moderator in the progress of atherosclerosis and exist long ahead the creation of atherosclerotic plaques [47]. Endothelial dysfunction is mostly triggered by decreased production or action of relaxing mediators. At this point, it is clear that reduced nitric oxide levels cause endothelial dysfunction in blood arterial walls which, leads to vasoconstriction of the artery [48]. and thus, increase blood pressure to high values (hypertension). In addition, it also, activates platelets leading to blood clotting, that increase the stimulation for artery walls inflammation, consequently, arterial walls penetrability to destructive lipoprotein, oxidized free radical species and various toxins is increased.

s-Klotho

α-Klotho protein is found extensively in human tissues of arteries, epithelium, endocrine system, and nerve tissues [49]. Molecular characteristic of Klotho is explained in detail by Martín- Nunez and colleagues, and therefore it is advised to the reader to look into this article [50]. Klotho appears in two forms; membrane and secreted, the membrane klotho acts as an necessitate coreceptor for fibroblast growth factor (FGF)-23, while secreted klotho regulates nitric oxide production in the endothelium. The extracellular domain of Klotho can be cleaved and cut in the circulation as s-Klotho where it may function as a blood vesselprotective hormone possibly by enhancing endothelial function [51,52] or, direct inhibition of arterial calcification [53]. Circulating s-Klotho is produced in the kidney predominantly expressed in renal distal tubular epithelial cells with implications in biological and anatomical processes, mainly in the cardiovascular arterial’s disease [16]. Early human aging that contains endothelial dysfunction, arterial calcification and progressive atherosclerosis were seen in mice lacking Klotho [17]. A reduction in Klotho levels is observed also in aged and physically inactive coronary artery disease patients [26]. These declines are demonstrated by a diminished ability for skeletal muscle to respond to physiological stimuli such as muscle loading or acute injury. Certainly, older adults often exhibit an age-related reduction in the number and size of muscle fibers known as sarcopenia [48]. Klotho appears to apply different functions in distinct cell types as nitric oxidereliant means, Klotho is a putative anti-aging gene, vital cofactor for the linkage of fibroblast growth factor (FGF 23) to its receptor, and thus, acting as a main controller of phosphate balance [18,54]. Studies on mouse genetics have revealed in vivo functions of Klotho (FGF signaling) [55,56].

The Klotho proteins and its connected enzyme β-Klotho apply various influences on the biological regulation of ion transport, energy metabolism, calcium and phosphate mainly by FGF-23 [57] In addition, s-Klotho functions as an obligate co-receptor with fibroblast growth factor receptor 1 (FGFR1) for fibroblast growth factor 23 (FGF23), a phosphaturic hormone essential for maintaining mineral homeostasis [58] Serum FGF-23 values are related to atherosclerotic problem, endothelial dysfunction, arterial stiffness and vascular calcification [59,60] Therefore, Klotho has been suggested as a master regulator of CAD [20,61]. Klotho inhibited the phosphatidyl nitric oxidesitol 3-kinase (PI3K)-AKT signaling pathway phosphorylation of fork head box protein O3a by improving its connection to the manganese superoxide dismutase supporter. Klotho increased mitochondrial manganese superoxide dismutase, mRNA and protein expression. In addition, Klotho reduce tacrolimus-induced oxidative stress and thus, converse mitochondrial dysfunction, consequently, decrease ROS production [56] Increased cellular levels of ROS result in damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis. Mice with Klotho-deficiency demonstrate an association with accelerated and enhanced development of vasculopathy [62] and early aging. However, increase Klotho expression increase genetic expression that solve the Klotho-deficient phenotype at baseline [16] and thus, improve mice’s standing against oxidant stress [63] In humans, serum levels of s-Klotho decrease after 40 years of age [25,64] this may be observed in sedentary individuals and patients with several aging-related diseases such as cardiovascular disease, cancer, hypertension, and kidney disease [65,66].

The clinical relations of s-Klotho and cardiovascular diseases were described earlier [67,68] suggesting that, s-Klotho values in the circulating blood in CAD patients are significantly lower compared to healthy matched peers. In addition, in community-dwelling adults higher plasma Klotho concentrations are independently associated with a lower likelihood of having CAD, heart failure, stroke, or peripheral arterial disease. Recently study by Saghiv, et al. [68] demonstrated that circulating s-Klotho levels are significantly higher while IGF-1 are significantly lower in aerobically trained CAD patients compared to untrained CAD patients and inactive healthy counter partners. Genetic variation studies have demonstrated that Klotho gene polymorphisms might be associated with longevity on one hand [16] and CAD on the other hand [69-71]. Previously Arking, et al. [72] suggested that, the functional of KL-VS allele, characterized by six SNPs is related to hypertension and stroke, and thus, it is a self-regulating risk factor for CAD [73].

Atherosclerosis reduction and cell protection occur by some antioxidant’s such as s-Klotho humoral. In addition, arterial stiffening may predispose the intima to atherosclerosis due to injury sustained from increased pulsatile pressure. In mice, klotho through humoral paths guards the arteries by nitric oxide produced in the endothelium [74]. The discovery of Klotho in human vessels tissue [75,76] increased the understanding about the role of the co-expression of two related FGF23 receptors, FGFR-1 and FGFR-3 [76]. Expression of Klotho protein seems to be restricted to arterial intima layer [78]. Yet an argument exists due to inconsistent data regarding Klotho presence in arterial tissue [79]. The connection of Klotho to endothelial dysfunction lays in the attenuation effect on endothelial dysfunction by ways of nitric oxide. Shimada, et al. [80] suggested, that lack of nitric oxide decrease angiogenesis in kl/kl mice and reduced endothelium-derived nitric oxide release, due to increased oxidative stress associated with aerobic exercise and aging. Klotho resists oxidative stress by the expression of manganese superoxide dismutase (Mn-SOD) through activation of FoxO forkhead also known as forkhead in rhabdomyosarcoma transcript factor [81] at the cellular and organismal level in mammals. FoxO forkhead is a human protein encoded by the FOXO3 gene [82] FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-binding domain [83]. Klotho protein stimulates the FoxO forkhead transcription factors that are negatively regulated by insulin/IGF-1 signaling, so bringing about an expression of manganese superoxide dismutase. With this content, Klotho increases nitric oxide formation through c-AMP-PKA-dependent pathway in human umbilical vascular endothelial cells, [19] and decreases (HO)2-prompt apoptosis and cellular senescence [83].

In addition, Klotho reduces oxidative stress production by limiting angiotensin II production [85] While the complete actions of angiotensin II signaling on NADPH oxidase are still under examination, angiotensin II, is an endogens peptide hormone, that has a major role in maintaining homeostasis in the cardiovascular system, as well as an effective stimulator of NADPH oxidase [86]. Recently Six, et al. [87] observed that attenuation of FGF23 or phosphate-induced vasoconstriction mediated by Klotho is eliminated by adding nitro-L-arginine, a competitive inhibitor of nitric oxide. Moreover, they observed that exposure of human umbilical vein endothelial cells to Klotho increased nitric oxide production and induced nitric oxide phosphorylation and the inducible isoform, nitric oxide, involved in immune response expression. Interestingly, Klotho was able to increase (HO)2 production in cultured human vascular smooth muscle cells, which suggests a more complex effect of this protein on the regulation of vascular tone through mediation of a ROS/ nitric oxide balance [87].

Aerobic Exercise

Physical inactivity decreases maximal oxygen uptake, muscle mass (sarcopenia), alters structural and intrinsic muscle cells and changes in energy availability which, decrease further with aging [88, 89]. Cardiac patients in a stage of myocardial deficiency usually lose their muscle mass and muscle strength, due to angiotensin II that directly affects the skeletal muscle and increases protein degradation [90]. Skeletal muscle atrophy is categorized by a reduction in protein contented, fiber width, force generation, and tiredness struggle ability [88]. In addition to angiotensin II, factor such as ROSs cause muscle protein degradation under different situations [88]. The existence of muscle atrophy points out of the rise in ROS production and the inability of antioxidant production to balance it resulting, in a reduced protein synthesis [91]. In addition, genetic factors regardless of lifestyle increase rate of biological aging process thereby, severely limiting elderly’s function, life quality and longevity [89,92]. However, regardless of age, gender or basal work capacity, aerobic exercise training is recommended as a tool to decrease rate of work capacity decline, typically arises as an individual age, being physically inactive or suffers from any cardiovascular disease [93].

Aerobic exercise was suggested as a nonpharmacological intervention in patients with cardiovascular disease in the main prevention and therapy of cardiovascular diseases [94,95]. It is recommended that exercise intensities be above the anaerobic threshold to vigorous exercise [96]. Yet, exercise mechanisms that slow down atherogenic progress have been completely understood. following long-lasting aerobic exercise, significant changes in the vascular are nitric oxide including decreased levels of C-reactive and inflammatory cytokines [97]. Aerobic exercise has the potential to minimize these pathological process’ and to reduce the amount of cardiovascular complications [35]. Effects of chronic aerobic exercise training in CAD and progression of coronary atherosclerosis patients is an increase in myocardial oxygen supply thus, reducing ischemic events. Some indications suggest that long-lasting aerobic exercise may avert loss in endothelium dependent vasodilation and increase levels in sedentary middle to older healthy men. This may represent an important mechanism by which regular aerobic exercise lowers the risk of cardiovascular disease in this population [98]. Aerobic training offers an epigenetic tendency which has benefits in cardiopulmonary and muscular functions, therefore, an individual must interact with environmental factors related to longevity, by exercising at moderate to high level of workloads [99]. In addition, long-lasting aerobic training lessens the decline in maximal oxygen uptake related to physical inactivity and aging [100].

The basic mechanism by which workout triggers genes (epigenetic) includes a stimulus signal to the DNA, then transcript through messenger RNA, and finally conversion into protein [101]. Previously it has been reported that oxidizing free radical species are generated during moderate and high aerobic bouts [102]. ROS production tops cellular defenses, under these conditions, in disease genetic and epigenetic regulation changes gene expression [103]. Skeletal muscle generates superoxide and nitric oxide during aerobic exercise in intensities above the anaerobic threshold [104]. ROS is essential for skeletal muscle force generation, however, ROS in high values may reduce muscle contraction properties and thus, bring about an early exhaustion [105]. There are plentiful indications that exercise can be operative in averting and suspending the result of age on muscle well-being and effectiveness. In addition, chronic exercise training intensifys nitric oxide production, that improves myocardial function due to the increase in coronary blood flow. In addition, nitric oxide has inhibitory effects on platelet and leukocytes well as induces proliferation of arterial smooth fibers [105]. Previous study demonstrate that long-lasting aerobic exercise training reduces cardiovascular risk factors [106]. The nitric oxide synthesis rate seems to be parallel related to increase in amino acid arginine availability [107]. The antithrombotic effect of Aerobic exercise decreases serum levels and activity of inflammatory factors, such as interleukin-6, C-reactive protein, and tumor necrosis factor-α, pointing out about the antithrombotic effect of aerobic exercise [108]. Following aerobic bout, blood pressure decreases to lesser levels than those recorded at rest, identified as post exercise hypotension [109]. This autoregulation mechanism response of aerobic exercise coupled with the nitric oxide vasodilator, affects positively the endothelium function and thus blood flow by decreasing total peripheral resistance [110, 111].

Although the association between s-Klotho and aerobic exercise training is not clear, recently, the α-Klotho gene is circulating in blood as s-Klotho have been related to the aerobic exercise [112,113]. Yet, exercise appears to take a major part on the secreted form of the α-Klotho gene in humans. In addition, α-Klotho gene is associated also with genes: β-Klotho gene and γ-Klotho gene, however, the last two mentioned genes do not have any role during exercise [114]. The increase in s-Klotho following aerobic exercise training may be a response to ROS that increase in muscle cells as a result of aerobic training. s-Klotho reduces apoptosis through the nitric oxide production and thus, suppress oxidative stress [115].

Interplay between Exercise, S-Klotho and Endothelial Dysfunction

Data suggests that endothelium plays a major part in the regulation of arterial stiffness by the action on smooth muscle tone affected by vasoactive intermediaries and, the effect of nitric oxide production on endothelin arterial stiffness [116]. Nitrogen nitric oxide is a soluble gas molecule with the chemical formula for NO. It is continually synthesized by the endothelium: L-arginine in endothelial cells is the precursor for nitric oxide synthesize by calcium-calmodulin-dependent enzyme nitric oxide synthase [117]. Nitric oxide acts as an endothelium-derived relaxing factor [118]. released from endothelial cells and acts as an inhibitor of ROS production, by decrease in L-arginine endogens asymmetric dimethyl-L-arginine ratio connected with endothelial dysfunction [119]. Nitric oxide stimulates phospholipase A2 and inhibitors of lysolecithin acyltransferase inducing smooth muscle tone relaxation by inhibiting low density lipoprotein oxidation [120]. Klotho has been linked to the prevention of muscle atrophy and cardiovascular disease in aged individuals [14]. Circulating s-Klotho acts as a humoral factor, involved in the endothelium production and regulation of nitric oxide. In turn, nitric oxide protects endothelial penetrability, smooth muscles’ contraction by calcium homeostasis and inhibits insulin-like growth factor-1 signaling [121].

Similar to Klotho’s anti-aging impacts have also been attributed to aerobic exercise [114, 122]. In recent years, there are enough studies regarding the effect of aerobic exercise on blood circulating s-Klotho [23,67] Reimers, et al. [123] demonstrated that the response of s-klotho depends on aerobic fitness level. In addition, levels of s-Klotho were significantly higher in trained individuals compared to untrained once [124]. suggesting that long lasting aerobic training may be an appropriate model for mechanistically probing the role of physical activity on s-Klotho expression. Populations aged 0 - 91 years, screened previously by ELISA revealed that the level of human s-Klotho declines with aging [125]. Previously in older mice, it has been demonstrated that low blood serum s-Klotho levels are related to reduced skeletal muscle strength and aerobic capacity [126]. On the other hand, trained elderly with aerobic capacity have longer life expectancies [127] and higher serum s-Klotho values compared to inactive elderly [112].

Moderate aerobic training attenuates aging-induced pathological cardiac hypertrophy at least partially by restoring s-Klotho levels, reduce oxidative stress, and lessening in the phosphorylation of ERK1/2, P38 and fibrosis [128]. The relationships between aerobic exercise, s-Klotho and endothelial dysfunction can be in brief described as follow: previously it has been suggested that s-Klotho and long-lasting aerobic exercise training are factors that may promote and upgrade young adults’ physical performance capacities [129]. Aerobic bout increases s-Klotho levels which in turn, increase FGF23 which promotes nitric oxide synthesis bringing about a, reduction in oxidative stress and ROS in skeletal muscle and accordingly, increase mitochondrial vitality and thus [130] attenuate restore endothelial dysfunction.

Conclusion

Recent developments point out on the effect of aerobic exercise training program as nitric oxide nonpharmacological mean to support in the treatment, prevention, and therapy of patients with cardiovascular diseases. The present review, suggests that aerobically active CAD patients, increase their Klotho gene expression, which may be a primary involvement to slow down endothelial dysfunction course and cardiovascular-related diseases. In addition, moderate aerobic exercise increase Klotho gene expression in muscle cells and decrease ROD production. Future research should examine the relationship between aerobic exercise training and circulating s-Klotho, on cardiovascular arterial stiffness and endothelial dysfunction.

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[irispublisherscardiovascular]

A Rare Manifestation of Common Disease: Cardiac Cirrhosis

Authored by Richmond R Gomes*

Abstract

The relation between diseased heart and liver may manifests as acute liver injury, chronic congestive hepatopathy, even cardiac cirrhosis. Congestive hepatopathy caused from impaired blood return to the right ventricle with increased filling pressure. Chronic liver disease (CLD) is the most frequent presentation of hepatobiliary disease. Very rare cause, like long term right heart failure may also be a cause of underlying disease for CLD. We present a case of a 54-year-old female with cardiac cirrhosis. Initial workup was negative. Later thoracic imaging and echocardiography showed chronic obstructive pulmonary disease (COPD) with evidence of pulmonary hypertension. We will briefly discuss the literature on cardiac causes of liver cirrhosis. Our case will present such a short report or cardio-hepatic relations.

Keywords:Congestive hepatopathy; Cardiac Cirrhosis; CLD; COPD; Pulmonary hypertension

Introduction

Chronic right sided congestive heart failure may cause chronic liver injury and cirrhosis of liver but is very uncommon. In long term right heart failure there is elevated venous pressure that is transmitted to liver sinusoids via inferior vena cava and hepatic veins. This leads to long term passive congestion and relative ischemia due to poor circulation eventually leading to necrosis and fibrosis of liver predominantly of centrilobular region. Patient generally presents with clinical features of congestive heart failure and portal hypertension but very rarely presents with variceal hemorrhage or encephalopathy [1]. But our case patient presented with evidence of variceal hemorrhage. Also, the overall prognosis of cardiac cirrhosis is not well established, and treatment of cardiac cirrhosis is mainly aimed at managing underlying heart failure, so it becomes important to distinguish it from other cause of cirrhosis1. The timely diagnosis of a cardiac etiology of liver dysfunction is important because such dysfunction is potentially reversible if the underlying cardiac disease is treated before the development of frank cirrhosis [2,3].

Case Report

A 54 year old lady, home maker, hailing from rural Bangladesh, not known to have diabetes, hypertension or coronary artery disease, chronic smoker (beedi-local hand-rolled cigarettes) presented with progressively increasing abdominal distension for last 6 months, bilateral leg swelling for 1 month and H/O two episodes of passage of black tarry stool since then. On repeated enquiry she also revealed of chronic cough and breathlessness with winter exacerbation for last 10 years and episodes of pedal edema relieving after local medicine. There was no history of alcohol intake, high risk sexual behavior, jaundice, tuberculosis, long term drug or herbal intake, surgery, or blood transfusion. There was no significant family history. On general examination patient was cooperative and well oriented with poor nutrition. Pallor, mild icterus, and bi-pedal pitting edema was present. Cyanosis, clubbing, lymphadenopathy were absent. Pulse-70/ min regular, microvolumes, normal in character and vessel wall normal. Blood pressure-100/ 70 mmHg. Neck vein was engorged, and pulsatile and jugular venous pressure raised. On abdominal examination, abdomen was distended diffusely with eversion of umbilicus and prominent veins in flanks and epigastrium with blood flow from below upwards. Abdominal striae were seen. There were no scar marks. No superficial tenderness present. Splenomegaly was present of 4 cm, firm, non-tender with smooth surface. Liver was also palpable 2 cm from right costal margin along right mid clavicular line, firm, tender with smooth surface and regular margin. No other lump present. Fluid thrill was present. On cardiovascular examination precordium seemed to be normal. Apex beat in 5th intercostal space 2 cm. Lateral to mid clavicular line normal in character. Thrill or para-sternal heave absent. On auscultation 1st and 2nd heart sound audible with loud pulmonary component of 2nd heart sound. The holosystolic, high-pitched, blowing murmur of tricuspid insufficiency best heard at the lower left sternal border. The murmur intensifies with inspiration and decreases with expiration. On respiratory examination chest bilaterally symmetrical with decreased movement on both sides. Trachea central and no deformity of spine seen. Respiratory rate of 26 /min. With use of accessory muscles seen. Vocal fremitus equal on both sides. Hyper-Resonant note heard on percussion. Bilaterally decreased breath sounds with diffuse rhonchi heard over lung fields. Vocal resonance decreased bilaterally. Nervous system examination reveals no abnormality.

Lab reports revealed: Heamoglobin-9.1 gm/dl, Total leucocyte count-3,800/dl, Differential count-neutrophil-58%, Lymphocytes-30%, Platelet’s count-117,000/dl. Random Blood sugar-6.6 mmol/L, Serum Sodium-131 mmol/l, Serum Potassium-4.1 mmol/l, Serum Creatinine-0.9 mg/dl Liver Function Test-S. Bilirubin-3.9 gm/dl, SALP-106 IU, SGPT-111 IU, Serum Protein—5.5 gm/dl, Serum Albumin-2.7 gm /dl Ascitic Fluid Examination—TLC-110/ cc, DLC-N35% L65%, Protein-1.3 gm/ dl, SAAG-1.4 ADA 12.1U/L (normal <30U/L) Prothrombin time: patient 18 secs, control 12 secs. Viral markers (HbsAg, HCV)— Negative Chest X-ray-Cardiac Enlargement with accentuation of bronchovesicular marking bilateral mild pleural effusion, ECG-Rate of 70/min with regular rhythm, ABG-pH-7.38, pCO2-65, pO2-74, SpO2-88%, USG Abdomen-Liver-17.16 cm, coarse parenchyma, Portal vein-12.9 mm & tortuous, Gross spleenomegaly—15.1 cm., Splenic vein—14.2 mm, tortuous & dilated with multiple collaterals in perihilar splenic region. Gross peritoneal collection. 2-D Echo- Grade 3 Tricuspid regurgitation, Severe Pulmonary Arterial Hypertension (PASP 40 mm Hg, dilated right ventricle and right atrium (Figure 1). Upper GI Endoscopy-Esophagus shows grade II × III columns of esophageal varices (Figure 2). Pro BNP was 15656 pg/ml (normal <400 pg/ml). TSH was normal (0.829 IU/ml, normal 0.350-3.40 IU/ml) Pulmonary Function Test-FEV1-52%, FVC-79%, FEV1/FVC-0.66 and improvement in FEV1 after use of bronchodilator was 7% suggesting of chronic obstructive airway disease stage II of GOLD criteria. Fibroscan of liver; Median stiffness was 37.4 Kpa, IQR/MED-10%, which correlate with stage-4 fibrosis, that is cirrhosis. Our final diagnosis was cardiac cirrhosis.She was started salt and fluid restrictions (daily 1000 ml/day) along with oral diuretics containing frusemide and spironolactone combination. Oral nitrates were advised to prevent further variceal bleeding as b-blockers are avoided in patients with respiratory airway diseases. Long acting b-agonist inhalers, montelukast and doxophyline were given to relieve broncho-constriction. Proton pump inhibitor prescribed to reduce acid production and prevent further damage due to acid reflux. Lactulose prescribed to prevent constipation and related complications. She was also transfused with 1 unit packed red cells and 4 units of fresh frozen plasma. Patient was given education regarding diet, precautions and follow up after discharge.

Discussion

Term cardiac cirrhosis denotes any type of hepatic fibrosis occurring in cardiac patient [4]. Our case report is in agreement with the previous observations of chronic liver injury due to long term congestive heart failure. It is a very uncommon cause of CLD and it’s difficult to distinguish from other causes of liver cirrhosis [5]. The most important mechanisms responsible for the development of congestive hepatopathy are hepatic congestion, decreased hepatic blood flow and hypoxemia 5 followed by atrophy, necrosis of hepatocytes, thrombi resulting due to cholestasis [6]. Causes of cardiac cirrhosis are valvular heart disease, cardiomyopathy, pericardial disease, ischemic heart disease, primary lung disease [7]. With decrease in incidence valvular heart disease, cardiomyopathy in etiology of cardiac cirrhosis has increased [8].

Our case had primary lung disease due to chronic smoking which resulted in pulmonary hypertension leading to chronic congestive heart failure. This further leads to passive congestion and relative ischemia due to poor circulation eventually leading to necrosis and fibrosis of liver predominantly of centrilobular region [9]. Usually, cases of cardiac cirrhosis do not develop variceal hemorrhage or encephalopathy, but our case had unusual presentation of melena suggesting variceal bleeding. Our case had Obstructive airway disease of stage II according to GOLD10 staging evidenced from deranged Pulmonary Function Test, Abnormal Blood Gas analysis. Evidence of Pulmonary hypertension was evident clinically in form of loud P2 and murmur of tricuspid regurgitation which was established on 2D Echocardiography. Chronic congestive heart failure established on long history of 5 years for which he is taking treatment (? diuretics) from quack of which records were not available and raised pro-BNP level.

Later he developed congestive hepatopathy and signs of portal hypertension as evidenced by splenomegaly, progressive ascites which was transudative with SAAG> 1.113, jaundice, dyspnea, engorged neck vein, hepatomegaly, pedal oedema, normal alkaline phosphatase levels, raised AST, ALT and serum bilirubin. Metabolic and synthetic functions of liver were also compromised evident from decreased serum albumin and deranged PT/INR [7]. In congestive hepatopathy, liver function tests do not show the specific pattern as in patient with hypoxic hepatopathy [11]. Cholestatic enzymes together with low albumin and high bilirubin are the strongest risk factor for poor outcome, in case of chronic heart failure [12]. Chest X-ray was suggestive of congestive cardiac failure as there was bilateral pleural effusion. Splenomegaly was associated with hypersplenism as evident from pancytopenia in blood picture. As our patient was suffering from chronic congestive heart failure and ascites, transabdominal liver biopsy is at risk and Transjugular liver biopsy is not practiced at our setting for the evaluation of cirrhosis. So, fibro scan was done, and result was suggesting liver cirrhosis. Usually, cases of cardiac cirrhosis does not develop variceal bleeding, but our case presented with variceal bleeding evident from history of melana which was established on upper gastro-intestinal endoscopy in which therapeutic banding could not be done due to financial constraints [13].

The timely diagnosis of a cardiac etiology of liver dysfunction is important because such dysfunction is potentially reversible if the underlying cardiac disease is treated before the development of frank cirrhosis [2,3]. Moreover, early treatment of underlying cardiac disease might also prevent the development of hepatocellular carcinoma as suggested by an interesting case study in which a patient with negative hepatitis serologies and cirrhosis secondary to constrictive pericarditis developed hepatocellular carcinoma confirmed by biopsy [14].

Conclusion

This case study illustrates to gastroenterologists the need to consider a cardiac etiology in the work-up of cirrhosis especially when the most common causes are not found. A patient with COPD developing chronic right sided heart failure due to pulmonary hypertension causes passive congestion on hepatic veins, eventually lead to hepatic fibrosis, and raised portal hypertension. Though variceal bleed is uncommon in portal hypertension due to cardiac cirrhosis but may be presenting complain in rare case as seen in our case. Thought COPD and cardiac cirrhosis both are very uncommon, our interest was to highlight the cardiac cause should be evaluated in a dysphonic adult, where the causes of CLD were not certain.

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[mcatmemoranda]

Liver biochemical and function tests – Blood tests commonly obtained to evaluate the health of the liver include liver enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, gamma-glutamyl transpeptidase), tests of hepatic synthetic function (albumin, prothrombin time/international normalized ratio [INR]), and the serum bilirubin level. (See 'Common liver biochemical and function tests' above.)

Initial evaluation of abnormal liver biochemical and function tests – The initial evaluation includes obtaining a history to identify potential risk factors for liver disease and performing a physical examination to look for clues to the etiology and for signs of chronic liver disease. Subsequent testing is determined based on the information gathered from the history and physical examination as well as the pattern of liver test abnormalities (table 4 and algorithm 1). (See 'Initial evaluation' above.)

●Patterns of liver test abnormalities – Liver biochemical test abnormalities can often be grouped into one of several patterns: hepatocellular, cholestatic, or isolated hyperbilirubinemia. Patients with a hepatocellular process generally have a disproportionate elevation in the serum aminotransferases compared with the alkaline phosphatase, while those with a cholestatic process have the opposite findings. The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two. Abnormal tests of synthetic function may be seen with both hepatocellular injury and cholestasis. (See 'Patterns of liver test abnormalities' above.)

●Patients with elevated serum aminotransferases – In the setting of hepatocyte damage, ALT and AST are released from hepatocytes, leading to increased serum levels. The differential diagnosis for elevated serum aminotransferases is broad and includes viral hepatitis, hepatotoxicity from drugs or toxins, alcoholic liver disease, hepatic ischemia, and malignant infiltration. The evaluation should take into account the patient's risk factors for liver disease as well as findings from the physical examination that may point to a particular diagnosis. The evaluation often involves testing for viral hepatitis and autoimmune disease (table 4). Occasionally, a liver biopsy may be required. (See 'Elevated serum aminotransferases' above.)

●Patients with cholestasis – Cholestasis may develop in the setting of extrahepatic or intrahepatic biliary obstruction (table 5). In patients with cholestasis, the alkaline phosphatase is typically elevated to at least four times the upper limit of normal. Lesser degrees of elevation are nonspecific and may be seen in many other types of liver disease, such as viral hepatitis, infiltrative diseases of the liver, and congestive hepatopathy. Patients with a predominantly cholestatic pattern typically undergo right upper quadrant ultrasonography to further characterize the cholestasis as intrahepatic or extrahepatic. (See 'Elevated alkaline phosphatase' above.)

The presence of biliary dilatation on ultrasonography suggests extrahepatic cholestasis which may be due to gallstones, strictures, or malignancy. The absence of biliary dilatation suggests intrahepatic cholestasis. There are numerous possible causes of intrahepatic cholestasis (table 5), including drug toxicity, primary biliary cholangitis, primary sclerosing cholangitis, viral hepatitis, cholestasis of pregnancy, benign postoperative cholestasis, infiltrative diseases, and total parenteral nutrition. Subsequent testing to identify the underlying cause may include checking antimitochondrial antibodies, magnetic resonance cholangiopancreatography, computed tomography, endoscopic ultrasonography, and/or endoscopic retrograde cholangiopancreatography (algorithm 1). (See 'Evaluation of elevated alkaline phosphatase' above.)

●Patients with isolated hyperbilirubinemia – The evaluation of isolated hyperbilirubinemia begins with determining whether the hyperbilirubinemia is predominantly conjugated (direct hyperbilirubinemia) or unconjugated (indirect hyperbilirubinemia). An increase in unconjugated bilirubin in serum results from overproduction, impairment of uptake, or impaired conjugation of bilirubin. The evaluation of unconjugated hyperbilirubinemia typically involves evaluation for hemolytic anemia as well as obtaining a history to determine if the patient has Gilbert syndrome. In a patient with a history consistent with Gilbert syndrome (eg, the development of jaundice during times of stress or fasting), normal serum aminotransferase and alkaline phosphatase levels, and mild unconjugated hyperbilirubinemia (<4 mg/dL), additional testing is not required. (See 'Isolated hyperbilirubinemia' above and 'Unconjugated (indirect) hyperbilirubinemia' above.)

An isolated elevation in conjugated bilirubin is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome, as well as other genetic bile transport disorders in children. Dubin-Johnson syndrome and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia (with a direct-reacting fraction of approximately 50 percent) in the absence of other abnormalities of standard liver biochemical tests. Normal levels of serum alkaline phosphatase and GGT help to distinguish these conditions from disorders associated with biliary obstruction. Differentiating between these syndromes is possible but clinically unnecessary due to their benign nature. (See 'Conjugated (direct) hyperbilirubinemia' above.)