Treatment of Jaundice; Risk Factors, Complications

Treatment of Jaundice
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Treatment of Jaundice/Jaundice is the commonest presentation of patients with liver and biliary disease. The cause can be established in most cases by simple non-invasive tests, but many patients will require referral to a specialist for management. Patients with high concentrations of bilirubin (>100 μmol/l) or with evidence of sepsis or cholangitis are at high risk of developing complications and should be referred as an emergency because delays in treatment adversely affect prognosis.

Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and whites of the eyes due to high bilirubin levels.[rx][rx] It is commonly associated with itchiness.[rx] The feces may be pale and the urine dark.[rx] Jaundice in babies occurs in over half in the first week following birth and in most is not a problem.[rx][rx] If bilirubin levels in babies are very high for too long, a type of brain damage, known as kernicterus, may occur.[rx]

Hyperbilirubinaemia is defined as a bilirubin concentration above the normal laboratory upper limit of 19 μmol/l. Jaundice occurs when bilirubin becomes visible within the sclera, skin, and mucous membranes, at a blood concentration of around 40 μmol/l. Jaundice can be categorized as prehepatic, hepatic, or posthepatic, and this provides a useful framework for identifying the underlying cause.

Types of Jaundice

There are three main types of jaundice

  • Hepatocellular jaundice –  occurs as a result of liver disease or injury.
  • Hemolytic jaundice –  occurs as a result of hemolysis, or an accelerated breakdown of red blood cells, leading to an increase in the production of bilirubin.
  • Obstructive jaundice – occurs as a result of an obstruction in the bile duct. This prevents bilirubin from leaving the liver.

Others

  • Physiologic jaundice – Physiologic jaundice occurs as a normal response to the baby’s limited ability to excrete bilirubin in the first days of life.
  • Breast milk jaundice – About 2 percent of breastfed babies develop jaundice after the first week. It peaks about two weeks of age and can persist up to three to 12 weeks. Breast milk jaundice is thought to be caused by a substance in the breast milk that increases the reabsorption of bilirubin through the intestinal tract.
  • Breastfeeding failure jaundice – It is caused by failure to initiate breastfeeding, resulting in dehydration, decreased urine production and accumulation of bilirubin. Late preterm infants, those who are born between 34 weeks and 36 weeks, are more susceptible to this problem because they do not have the coordination and strength to maintain a successful breastfeeding. However, it is also very common in full-term newborns and usually gets better once breastfeeding is established.
  • Jaundice from hemolysis – Jaundice may occur with the breakdown of red blood cells due to hemolytic disease of the newborn (Rh disease), or from having too many red blood cells that break down naturally and release bilirubin.
  • Jaundice related to inadequate liver function – Jaundice may be related to inadequate liver function due to infection or other factors.

Causes of Jaundice

Hemolytic

Intrinsic causes of hemolysis

Membrane conditions

  • Spherocytosis
  • Hereditary elliptocytosis

Enzyme conditions

  • Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
  • Pyruvate kinase deficiency

Globin synthesis defect

  • sickle cell disease
  • Alpha-thalassemia, e.g. HbH disease

Extrinsic causes of hemolysis

Systemic conditions

  • Sepsis
  • Arteriovenous malformation

Alloimmunity (The neonatal or cord blood gives a positive direct Coombs test and the maternal blood gives a positive indirect Coombs test)

  • Hemolytic disease of the newborn (ABO)
  • Rh disease
  • Hemolytic disease of the newborn (anti-Kell)
  • Hemolytic disease of the newborn (anti-Rhc)
  • Other blood type mismatches causing hemolytic disease of the newborn

Non-hemolytic causes

  • Breastfeeding jaundice
  • Breast milk jaundice
  • Cephalohematoma
  • Polycythemia
  • Urinary tract infection
  • Sepsis
  • Hypothyroidism
  • Gilbert’s syndrome
  • Crigler-Najjar syndrome
  • High GI obstruction (Pyloric stenosis, Bowel obstruction)

Conjugated (Direct) Liver causes

Infections

  • Sepsis
  • Hepatitis A
  • Hepatitis B
  • TORCH infections

Metabolic

  • Galactosemia
  • Alpha-1-antitrypsin deficiency, which is commonly missed, and must be considered in DDx
  • Cystic fibrosis
  • Dubin-Johnson Syndrome
  • Rotor syndrome
  • Drugs
  • Total parenteral nutrition
  • Idiopathic

Post-liver

Biliary atresia or bile duct obstruction

  • Alagille syndrome
  • Choledochal cyst

Drugs that may cause liver damage

Analgesics

  • Paracetamol
  • Aspirin
  • Non-steroidal anti-inflammatory drugs

Cardiac drugs

  • Methyldopa
  • Amiodarone

Psychotropic drugs

  • Monoamine oxidase inhibitors
  • Phenothiazines (such as chlorpromazine)

Others

  • Sodium valproate
  • Oestrogens (oral contraceptives and hormone replacement therapy)

Important risk factors for severe hyperbilirubinemia in infants at ≥ 35 weeks’ gestation

  • Predischarge total serum or transcutaneous bilirubin measurement in the high-risk or high–intermediate-risk zone
  • Lower gestational age
  • Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive
  • Jaundice observed in the first 24 hours
  • Isoimmune or other hemolytic diseases (e.g., G6PD deficiency)
  • Previous sibling with jaundice
  • Cephalohematoma or significant bruising
  • East Asian race

 Pediatrics 2009;124:1193–8. Copyright © 2009 American Academy of Pediatrics.

Hyperbilirubinemia neurotoxicity risk factors [in addition to lower gestational age]

  • Isoimmune hemolytic disease
  • G6PD deficiency
  • Asphyxia
  • Sepsis
  • Acidosis
  • Albumin < 3.0 mg/dL [< 0.03 g/L]

Pediatrics 2009;124:1193–8. Copyright © 2009 American Academy of Pediatrics.

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Symptoms of Jaundice

Common symptoms of jaundice include:

  • A yellow tinge to the skin and the whites of the eyes, normally starting at the head and spreading down the body
  • Pale stools
  • Dark urine
  • Itchiness

Accompanying symptoms of jaundice resulting from low bilirubin levels include:

  • Fatigue
  • Abdominal pain
  • Weight loss
  • Vomiting
  • Fever
  • In these cases, yellowing may be more obvious elsewhere, such as:
  • On the palms of their hands
  • On the soles of their feet
  • Inside their mouth
  • Not want to feed or not feed as well as usual
  • Have dark, yellow pee (it should be colorless)
  • Have pale poo (it should be yellow or orange)

Diagnosis of Jaundice

The History

  • Duration of jaundice
  • Previous attacks of jaundice
  • Pain
  • Chills, fever, systemic symptoms
  • Itching
  • Exposure to drugs (prescribed and illegal)
  • Biliary surgery
  • Anorexia, weight loss
  • Colour of urine and stool
  • Contact with other jaundiced patients
  • History of injections or blood transfusions
  • Occupation

Differential diagnosis of neonatal cholestatic liver disorders

Structural

  • Extrahepatic biliary atresia
  • Choledochal cyst
  • Caroli’s syndrome
  • Choledocholithiasis
  • Alagille’s syndrome
  • Nonsyndromic bile duct paucity
  • Undersized extrahepatic biliary system (biliary hypoplasia)
  • Neonatal sclerosing cholangitis

InfectionViral

  • Bacterial infection (sepsis or remote from liver [eg, urinary tract infection])
  • Toxoplasmosis
  • Syphilis
  • Metabolic
  • Alpha-1-antitrypsin deficiency
  • Galactosemia
  • Tyrosinemia
  • Hereditary fructose intolerance
  • Glycogen storage disease type IV

Lipid storage disease

  • – Niemann-Pick disease type A
  • – Niemann-Pick disease type C
  • – Gaucher’s disease
  • – Wolman’s disease
  • Mitochondrial enzymopathies (including fatty acid oxidation disorders)
  • Peroxisomal disorders (eg, Zellweger syndrome)
  • Bile acid synthesis disorders

Progressive familial intrahepatic cholestasis syndromes

  • – FIC-1 protein deficiency (PFIC 1)
  • – Bile salt export pump deficiency (PFIC 2)
  • – MDR3 protein deficiency (PFIC 3)
North American Indian familial cholestasis
  • Urea cycle defects
  • Genetic
  • Cystic fibrosis
  • Trisomy 21Trisomy 18
  • Neoplastic
  • Neuroblastoma
  • Hepatoblastoma
  • Histiocytosis toxic

Drug-induced

  • Total parenteral nutrition
  • Endocrine
  • Panhypopituitarism
  • Hypothyroidism
  • Neonatal lupus erythematosus
  • VascularBudd-Chiari syndrome
  • Congestive heart failure
  • Hepatic hemagiomatosisIdiopathic
  • Initial investigations for conjugated hyperbilirubinemia

Blood

  • Liver panel: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, conjugated bilirubin and albumin
  • Coagulation studies (prothrombin time/international normalized ratio, partial thromboplastin time)
  • Complete blood count and differential with a smear
  • Toxoplasmosis, other infections, rubella, Cytomegalovirus infection and herpes simplex (TORCH) serology
  • Blood culture
  • Hepatitis B surface antigenGlucose/serum lactate/serum amino acids/ammonia
  • Thyroxine, thyroid-stimulating hormone
  • Iron studies, ferritin
  • Galactosemia screen

Urine

  • Reducing substances
  • Organic acids
  • Bacterial culture
  • Urine Cytomegalovirus (positive result before four weeks of age is highly suggestive of congenital Cytomegalovirus
  • Conjugated bilirubin present, urobilinogen > 2 units but variable (except in children). Kernicterus is a condition not associated with increased conjugated bilirubin.
  • Plasma protein show characteristic changes.
  • Plasma albumin level is low but plasma globulins are raised due to an increased formation of antibodies.

Imaging Test

  • Ultrasonography –  is the first line imaging investigation in patients with jaundice, right upper quadrant pain, or hepatomegaly. It is non-invasive, inexpensive, and quick but requires experience in technique and interpretation. Ultrasonography is the best method for identifying gallbladder stones and for confirming extrahepatic biliary obstruction as dilated bile ducts are visible. It is good at identifying liver abnormalities such as cysts and tumors and pancreatic masses and fluid collections, but visualization of the lower common bile duct and pancreas is often hindered by overlying bowel gas. Computed tomography is complementary to ultrasonography and provides information on liver texture, gallbladder disease, bile duct dilatation, and pancreatic disease. Computed tomography is particularly valuable for detecting small lesions in the liver and pancreas.
  • Cholangiography –  identifies the level of biliary obstruction and often the cause. Intravenous cholangiography is rarely used now as opacification of the bile ducts is poor, particularly in jaundiced patients, and anaphylaxis remains a problem. Endoscopic retrograde cholangiopancreatography is advisable when the lower end of the duct is obstructed (by gallstones or carcinoma of the pancreas). The cause of the obstruction (for example, stones or parasites) can sometimes be removed by endoscopic retrograde cholangiopancreatography to allow cytological or histological diagnosis.
  • Percutaneous transhepatic cholangiography – is preferred for hilar obstructions (biliary stricture, cholangiocarcinoma of the hepatic duct bifurcation) because better opacification of the ducts near the obstruction provides more information for planning subsequent management. Obstruction can be relieved by insertion of a plastic or metal tube (a stent) at either endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography.
  • Magnetic resonance cholangiopancreatography – allows non-invasive visualization of the bile and pancreatic ducts. It is superseding most diagnostic endoscopic cholangiopancreatography as faster magnetic resonance imaging scanners become more widely available.
  • Liver biopsy – Percutaneous liver biopsy is a day case procedure performed under local anesthetic. Patients must have a normal clotting time and platelet count and ultrasonography to ensure that the bile ducts are not dilated. Complications include bile leaks and hemorrhage, and overall mortality is around 0.1%. A transjugular liver biopsy can be performed by passing a special needle, under radiological guidance, through the internal jugular vein, the right atrium, and inferior vena cava and into the liver through the hepatic veins.
  • Measurement of Bilirubin Levels – Bilirubin level can be checked through the biochemical method, Bilimeter or transcutaneous bilirubinometer ().
  • Biochemical – The gold standard method for bilirubin estimation is the total and conjugated bilirubin assessment based on the van den Bergh reaction ([.
  • Millimeter – Spectrophotometry is the base of Bilimeter and it assesses total bilirubin in the serum. Because of the predominant unconjugated form of bilirubin, this method has been found a useful method in neonates.
  • Transcutaneous Bilirubinometer – This method is noninvasive and is based on the principle of multi-wavelength spectral reflectance from the bilirubin staining in the skin [. The accuracy of the instrument may be affected by the variation of skin pigmentation and its thickness [.
  • Clinical Approach to Jaundice – The initial step in the evaluation of any newborn for jaundice is to differentiate between physiological and pathological jaundice. A helpful algorithm as adapted by AAP (2004b) [ is as follows.
  • Dependency on Newborn Period or Preterm – Preterm intervention values are different and depend on the degree of prematurity and birth weight [.
  • Evidence of Hemolysis – Onset of jaundice within 24 h, presence of pallor and hydrops, presence of hepatosplenomegaly, presence of hemolysis on the smear of peripheral blood, increased count of reticulocyte (>8%), rapid rise of bilirubin (>5 mg/dl in 24 h or >0.5 mg/dl/hr) or a family history of considerable jaundice should create a suspicion of hemolytic jaundice [.
  • Instructions and Precautionary Measure for Parents during Physiological Jaundice – The benign nature of jaundice should be explained and demonstrated to the parents. The mother should be encouraged to breast-feed her baby frequently and exclusively, at least eight to twelve times per day for initial several days, with no top feeds or glucose water whatsoever [. The mother should be told to bring the baby to the hospital if the color on the legs looks as yellow as the face.
  • Abdominal sonography is a valuable screening test in the jaundiced patient [. The demonstration of biliary ductal dilation, gallstones, hepatic mass lesion, or an enlarged or abnormally shaped pancreas directs further investigation or therapy. Sonography is noninvasive, readily available in most hospitals, does not involve radiation exposure, and is cheaper than CT or other procedures in which the bile ducts are directly opacified. It may also allow guided biopsy or drainage of lesions in the liver or pancreas. However, sonography may be technically unsatisfactory in up to 40% of cases, primarily due to obesity or to the accumulation of bowel gas, which prevents transmission of sound waves.
  • Hepatobiliary scintigraphy – had little to contribute to the differential diagnosis of jaundice except in the instance of neonatal hepatitis versus biliary atresia or the occasional need for objective assessment of liver size. However, the development of new radionuclide agents with improved hepatic extraction and biliary excretion, improved imaging techniques, and the application of computer assistance to the interpretation of dynamic scans have transformed HBS into an accurate modality for the diagnosis of large bile duct obstruction and may also prove useful in demonstrating intrahepatic cholestasis[.
  • Percutaneous transhepatic cholangiography – involves passage of a thin needle into the liver under fluoroscopic guidance and injection of contrast into the biliary tree [. The procedure is easily available, its cost is generally less than that of ERCP, and a local anesthetic injection over the right flank is the only sedative or anesthetic medication required. Dilated ducts are opacified in 95 to 100% of cases, but even nondilated ducts are opacified in 60 to 95% of cases. A dilated, the obstructed duct may be decompressed percutaneously by the passage of a guide wire and cannula through the right flank incision.
  • Endoscopic retrograde cholangiopancreatography – is performed by passing a flexible fiberoptic endoscope into the patient’s duodenum, inserting a cannula into the pancreatic and common bile ducts and injecting radiopaque contrast into these structures under fluoroscopy [. ERCP has the advantage of visualization and potential biopsy of the stomach and duodenum (since the scope is side-viewing. the esophagus cannot be seen). The procedure diagnoses pancreatic carcinoma in at least 90% of cases and can furnish visual (photographic and radiographic) and histologic proof of ampullary tumors.
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Treatment of Jaundice

Key elements from the American Academy of Pediatrics guideline on the management of hyperbilirubinemia in the newborn at ≥ 35 weeks’ gestation

  • Promote and support successful breastfeeding
  • Establish nursery protocols for the identification and evaluation of hyperbilirubinemia
  • Measure the total serum or transcutaneous bilirubin level in infants with jaundice in the first 24 hours
  • Recognize that visual estimation of the degree of jaundice can lead to errors, particularly in darkly pigmented infants
  • Interpret all bilirubin levels according to the infant’s age in hours
  • Recognize that infants at less than 38 weeks’ gestation, particularly those who are breastfed, are at higher risk of hyperbilirubinemia and require closer surveillance and monitoring
  • Perform a systematic assessment on all infants before discharge for the risk of severe hyperbilirubinemia
  • Provide parents with written and verbal information about jaundice in the newborn
  • Provide appropriate follow-up based on the time of discharge and the risk assessment
  • Treat jaundice in the newborn, when indicated, with phototherapy or exchange transfusion

The treatment options for jaundice include phototherapy further subdivided to conventional, intensive and exchange transfusion, and pharmacological treatment subdivided to phenobarbitone, intravenous immunoglobulins (IVIG), metalloporphyrins and follow up remedies [.

Phototherapy

Hyperbilirubinemia can be treated easily without or with a minimal adverse effect with phototherapy [. The efficacy of phototherapy depends on surface area exposed to phototherapy: Double surface phototherapy may be more effective than single surface phototherapy [. The spectrum of light source: Special blue tubes with the mark F20T12/BB should be used rather than F20T12/B lights and Irradiance or energy output may be increased in a phototherapy unit by lowering the distance of the neonate to within 15–20 cm [. Continuous phototherapy is better than intermittent phototherapy. Phototherapy should not be interrupted except during breastfeeding or nappy change [.

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Conventional Phototherapy

  • One can use conventional or fiber-optic phototherapy units provided jaundice is non-hemolytic or its progression is slow.

Intensive Phototherapy

  • In the circumstances including hemolytic jaundice, rapidly increasing bilirubin, or ineffectiveness of a conventional unit, using intensive phototherapy is warranted. Placing the baby on the bili-blanket and using additional overhead phototherapy units contain blue lights and then lowering the phototherapy units to within a distance of 15–20 cm are two significant remedies [.

Exchange Transfusion

Through exchange transfusion, bilirubin and hemolytic antibodies are removed [.

  • Rh Isoimmunization – Always, Blood using for exchange transfusion should be negative Rh isoimmunization, negative for Rh factor. O (Rh) negative packed cells suspended in AB plasma will be the best choice. O (Rh) negative whole blood or cross-matched baby’s blood group (Rh negative) may also be used in an emergency [.
  • ABO Incompatibility – Only O-blood group should be used for exchange transfusion in newborns with ABO incompatibility. The best choice would be O group (Rh compatible) packed cells which are suspended in O group/AB plasma whole blood (Rh compatible with baby).
  • Other situations – In the case of the Cross-matched with baby’s blood group blood volume used or double volume exchange should be kept in mind.
  • Blood Volume Used –  Partial exchange is done at birth in Rh hemolytic disease: 50-ml/kg of packed cells
  • Double Volume Exchange  2 × (80–100 ml/kg) &times birth weight (kg)

Pharmacological Treatment

Pharmacological treatment of neonatal jaundice can further be categorized into different subheadings such as phenobarbitone, Intravenous immunoglobulins, and Metalloporphyrins etc. [.

Phenobarbitone

  • Bilirubin processing including hepatic uptake, conjugation, and its excretion are ameliorated by this agent thus helps in decreasing level of bilirubin. However,r the effect of phenobarbitone is not rapid and takes time to show. When used for 3–5 days in a dose of 5 mg/kg after birth prophylactically, it has shown to be effective in babies with hemolytic disease, extravasated blood and in pre-term without any significant side effects. There is a huge literature documenting the efficacy and mechanism of action and complications of treatment for Phenobarbital [.

Intravenous Immunoglobulin (IVIG)

  • High dose IVIG (0.5–1 gr/kg) has shown to be effective in decreasing the needs of exchange transfusion and phototherapy in babies with Rh hemolytic disease [.

Metalloporphyrins

  • These compounds are still experimental but showing promising results in various hemolytic and non-hemolytic settings without significant side effects [.

Fiber-optic blanket

  • Another form of phototherapy is a fiberoptic blanket placed under the baby. This may be used alone or in combination with regular phototherapy.

Exchange transfusion to replace the baby’s damaged blood with fresh blood

  • Exchange transfusion helps increase the red blood cell count and lower the levels of bilirubin. An exchange transfusion is done by alternating giving and withdrawing blood in small amounts through a vein or artery. Exchange transfusions may need to be repeated if the bilirubin levels remain high.

Adequate hydration with breastfeeding or pumped breast milk. 

  • The American Academy of Pediatrics recommends that, if possible, breastfeeding be continued. Breastfed babies receiving phototherapy who are dehydrated or have excessive weight loss can have supplementation with expressed breast milk or formula.

Follow-up

  • Babies having roughly 20 mg/dl serum bilirubin and that requiring exchange transfusion should be kept under follow-up in the high-risk clinic for neurodevelopmental outcome [. Hearing assessment (Brainstem Evoked Response Audiometry (BAER)) should be done at 3 months of corrected age [.

Risk factors

Underlying conditions that may cause jaundice to include

  • Acute inflammation of the liver – This may impair the ability of the liver to conjugate and secrete bilirubin, resulting in a buildup.
  • Inflammation of the bile duct – This can prevent the secretion of bile and removal of bilirubin, causing jaundice.
  • Obstruction of the bile duct – This prevents the liver from disposing of bilirubin.
  • Hemolytic anemia – The production of bilirubin increases when large quantities of red blood cells are broken down.
  • Gilbert’s syndrome – This is an inherited condition that impairs the ability of enzymes to process the excretion of bile.
  • Cholestasis –This interrupts the flow of bile from the liver. The bile containing conjugated bilirubin remains in the liver instead of being excreted.
  • Crigler-Najjar syndrome – This is an inherited condition that impairs the specific enzyme responsible for processing bilirubin.
  • Dubin-Johnson syndrome – This is an inherited form of chronic jaundice that prevents conjugated bilirubin from being secreted from the cells of the liver.
  • Pseudojaundice – This is a harmless form of jaundice. The yellowing of the skin results from an excess of beta-carotene, not from an excess of bilirubin. Pseudojaundice usually arises from eating large quantities of carrot, pumpkin, or melon.

REferences

Treatment of Jaundice

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    God so loved the world that He gave us His only begotten son, so that whoever believes in Him, through faith, shall not perish, but have everlasting life. Jesus says if we wish to enter into life to keep the commands! The two greatest commands are to love God with all your heart, soul, strength, and mind; and your neighbor as yourself. All the law hang on these commands. We must be born of and lead by the Holy Spirit, to be called children of God, to inherit the kingdom. If we are willing to humble ourselves in prayer to Jesus, to confess and forsake our sins, He is willing to give the Holy Spirit to those who keep asking of Him; giving us a new heart, leading us into all truth!

    Jesus came to free us from the bondage of sin. The everlasting fire was prepared for the devil and his angels due to disobedience to God’s law. If we do the same, what makes us any different than the devil? Jesus says unless we repent, we shall perish. For sin is the transgression of the law. We must walk in the Spirit so we may not fulfill the lusts of the flesh, being hatred, fornication, drunkenness and the like. Whoever practices such things will not inherit the kingdom (Galatians 5:16-26). If we sin, we may come before Jesus to ask for forgiveness (1 John 2:1-2). Evil thoughts are not sins, but rather temptations. It is not until these thoughts conceive and give birth by our own desires that they become sin (James 1:12-15). When we sin, we become in the likeness of the devil’s image, for he who sins is of the devil (1 John 3:8); but if we obey Jesus, in the image of God. For without holiness, we shall not see the Lord (Hebrews 12:14).

    The oldest religion in the world is holiness through faith (James 1:27). What religion did Adam and Eve follow before the fall? Jesus, Who became the last Adam, what religion does He follow? Is He not holy? He never told us to follow the rituals and traditions of man but to take up our cross and follow Him (Luke 9:23). There are many false doctrines being taught leading people astray. This is why we need the Holy Spirit for discernment. Unlike religion, holiness cannot be created. It is given to us from above by the baptism of the Spirit. Jesus is more than a religion; He is about having a personal relationship with the Father. Start by reading the Gospel of Matthew, to hear the words of God, to know His character and commandments. Follow and obey Jesus, for He is the way, the truth, and the life!

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