Ch. Trochomatis

 

•  Pelvic inflammatory is most commonly caused by Chlamydia trachomatis and Neisseria gonorrhoeae.
• C. trachomatis is an obligate intracellular organism.
• Obligate intracellular organisms are best combated by a strong cellular immune response.
• CD 4+ Th1 cells promote a cellular immune response.
• T-bet is the master transcription factor for Th1 cells.
• It can cause cervicitis, urethritis, and proctitis
• In women, these infections can lead to 
• Pelvic inflammatory disease PID
• tubal factor infertility
• ectopic pregnancy 
• chronic pelvic pain
• Lymphogranuloma venereum (LGV) is another type of STD caused by C. trachomatis. LGV is the cause of recent proctitis outbreaks among gay, bisexual, and other men who have sex with men (MSM) worldwide.

Gabapentin (Neurontin) Side Effects

 Following side effects are associated with Gabapentin use.

• Dizziness
• Suicidal thoughts
• Respiratory depression
• Dementia and mild cognitive impairment

peau d'orange

 Peau d'orange

Pharyngitis in Primary Care

 Pharyngitis in Primary Care

Loss of Vision

https://www.gponline.com/loss-vision-red-flag-symptoms/article/1911296?bulletin=bulletins%2F60secondgp&utm_medium=EMAIL&utm_campaign=eNews%20Bulletin&utm_source=20250405&utm_content=60-Second%20GP%20(24)::&email_hash= 

Neonatal Lupus

 https://www.nejm.org/doi/full/10.1056/NEJMicm2415348?query=WB

Melanoma - Four warning signs

 

• Roughly 100,640 Americans will be diagnosed with melanoma this year, according to the  American Cancer Society, making it one of the most common types of cancer in the U.S., especially among older adults who have endured decades of sun exposure and whose immune systems aren't robust as they once were.
• The good news: Melanomma is highly curable if it's caught early.
• The hallmarks of melanoma are asymetrical or rough-looking moles without clearly defined borders.
• A spot on the skin that contienus to grow in size or change is another indication, and a once-monthly body scan is an easy way to keep tabs on any of these concerning characteristics.
• The ugly duckling: People who ave lots of moles are at increased risk for melanoma. That doesn't mean, however, that you need to panic over every mark on your body. Pay attention to the moles that stand out those that are darker than the rest, have changed recently or are more oddly shaped. Some oncologist called them Ugly Duckling. With women, melanomas most commonly appear on the arms and legs. Men need to pay special attention to their head, neck, back and trunk. Still, those aren't the only places this type of skin cancer can pop up.
• Where the sun doesn't shine: The majority of melanomas are thought to be caused by ultravioet (UV) light, but not all of them come from sun exposure. Melanoma can develop anywhere on the body, including " in places the sun doesn't shine" like the soles of the feet or the palm of the hand. The cancer can also appear as a dark streak under a fingernail or toenail, which is what happened to musician Bob Marley. He initially mistook his melanoma for a bruise on the toe and eventually died from it. And while it's rarer, melanoma also can develop on the eye, inside the mouth or on the scalp, Patients experience changes in their hair color " someone who had gray hair and developed a black streak, because of a melanoma growing on the scalp. So, strange things can happen, but these aren't common ones. The hidden melanomas are more common in people with darker skin. Black and Indian and Asian patients have nail changes, any dark spots on the palms and soles, as well as in the eye and mouth, these are ones that need to be worry about.Melanoma is 20 times more common in white individuals than in Black individuals, according to te American Cancer Society. Howevery, when melanoma develops in people of color, it's often diagnosed at a later more dangerous stage. A 2019 study from the CDC found that the ive-year melanoma survival rate amond non-Hispanic Balck populations was 66.2 percent, compared with 90.1 percent for non-Hispanic white populations.
• Red, white and blue hues Melanomas are often depicted as dark-brown moles, but they can acutally present in a variety of colors. The cancer may have a blue tint to it, from deeper pigmentation. or it can appear red, the result of an immune response. Melanoma also appear like a rash. Another sign of a melanoma can be lack of color. Some of these cancerous spots lose their pigmentation completely or partially, leaving a halo of white around a darker spot.
• Spots on the skin that bleed or itch: Sometimes a mole on the body starts to itch or becomes more painful or tender. The same goes if the surface of a molre changes, maybe it starts to ooze or bleed or take on a scalier appearance and doesn't heal on its own.Itching, bleeding and irritation near the actual mole are red flags.

Oedema - red flag symptoms

 

Red flag symptoms to be aware of when a patient presents with pitting or non-pitting oedema in primary care.

Red flag symptoms

• Abdominal distention
• Breathlessness, paroxysmal nocturnal dyspnoea and/or orthopnoea
• Change in medication
• Chest pain
• Hypertension
• Pain, hyperpigmentation, and absent leg pulse
• Periorbital oedema in a child
• Significant discrepancy in leg size
• Signs of sepsis
• Symptoms suggestive of alcohol misuse
• Symptoms suggestive of Cushing's syndrome
• Symptoms suggestive of hypothyroidism    

Presentation

An adult male, weighing 70kg, typically has about 12 litres of interstitial fluid and would need to have an increase of about 2 litres (15%) before this becomes visibly apparent as clinical oedema.

As a result of gravity, this would be noticed most easily over the ankles when mobile, or over the sacrum if bed-bound.

Causes of oedema

Several physiological states can increase the chance of oedema occurring, such as dehydration, immobility, pregnancy, timing in the menstrual cycle, or obesity.

Pitting oedema
Pitting oedema can be a sign of dysfunction in a range of organs or organ systems. Decreased oncotic pressure in the liver, kidneys, or gastrointestinal tract is often triggered by protein loss somewhere, such as:

• allergies
• inflammatory bowel disease
• liver cirrhosis
• malabsorption
• nephrotic syndrome
• starvation
• tumours

Oedema in children is most commonly caused by nephrotic syndrome, and it usually presents with periorbital oedema.

Two-thirds of patients with a deep vein thrombosis (DVT) may end up with a late complication of post-thrombotic syndrome, which can increase oedema, pain, hyperpigmentation, and even skin ulceration.

Rapid onset of new pitting oedema is most likely related to (new) medication, commonly NSAIDs, calcium antagonists, steroids, or insulin. If there are systemic symptoms, such as breathlessness, then an acute cardiac cause is among the most likely reasons until proven otherwise.

Consider local infection, inflammation, trauma, or venous thromboembolism if pitting oedema is more localised and perhaps unilateral.

Idiopathic pitting oedema is a diagnosis of exclusion.

Non-pitting oedema
Non-pitting oedema can develop in cases of hypothyroidism – through mucopolysaccharide deposition – or lymphoedema (often traumatic; after injury, radiation, surgery, malignant infiltration, infection, and so on).

Angioedema can also be a cause.

Unilateral versus bilateral

Unilateral

• Chronic venous insufficiency
• Compression
  
  • compartment syndrome
  • tumours
  • varicose veins

• DVT
• Infection
• Obesity
• Trauma

Bilateral

• Acute renal failure, nephrotic syndrome
• Compression
  
  • intra-abdominal
  • pelvic

• Cor pulmonale
• Heart failure
• Idiopathic
• Liver cirrhosis
• Medications
• Obesity
• Pregnancy
• Sepsis

Examination

Establish whether there are any signs to suggest an acute process or emergency. Check the legs for pulses, skin changes, differences in circumference, and redness.

In cases of suspected cardiac oedema, check (bilateral) blood pressure, jugular venous pressure, oxygen saturation and pulse (auscultate both lung bases for fine crackles indicative of pulmonary oedema). Do not miss possible ascites during abdominal examination.

Do a urine dipstick.

Blood tests should include:

• D-dimer
• FBC
• U&E
• LFT and gamma-glutamyl transferase
• consider inflammation markers: TFTs, urate, BNP (as needed).

Other tests to consider:

• arterio-venous pressure measurement
• abdominal ultrasound
• chest X-ray
• ECG
• Echocardiogram
• pelvic duplex or doppler scan.

In suspected DVT, refer acutely (to local pathways) for confirmation of diagnosis and initial management.

Management

Review current medication.

Consider any contributing factors including diet (protein) and fluid intake/loss and advise accordingly.

Establish whether the oedema needs any medical treatment and, if so, how urgently. Involve specialists as required, particularly for oedema in children.

Empirical treatment with diuretics is usually inappropriate, especially if the diagnosis is not yet clear and if there are no other symptoms.

Visit MIMS Learning for an interactive version of this article and a CPD certificate

• This article was originally written by Dr Anna Cumisky and was updated in 2019 by Dr Tillmann Jacobi, and again in March 2024 by Dr Pipin Singh a GP in Northumberland

Antibiotics - Mechanism of Action

 

Chlamydia Trachomatis

•  Pelvic inflammatory is most commonly caused by Chlamydia trachomatis and Neisseria gonorrhoeae.
• C. trachomatis is an obligate intracellular organism.
• It can cause cervicitis, urethritis, and proctitis
• In women, these infections can lead to 
• Pelvic inflammatory disease PID
• tubal factor infertility
• ectopic pregnancy 
• chronic pelvic pain
• Lymphogranuloma venereum (LGV) is another type of STD caused by C. trachomatis. LGV is the cause of recent proctitis outbreaks among gay, bisexual, and other men who have sex with men (MSM) worldwide.

Octreotide

• Octreotide is a synthetic somatostatin analog that inhibits multiple hormones including vasoactive intestinal polypeptide (VIP), luteinizing hormone, growth hormone, glucagon & insulin.

Granulosa Cell Tumors

•  Granulosa cell tumors develop from granulosa cells & may actively secrete estrogens.

Tularemia

• Tularemia is caused by Francisella Tularensis.
• Fifty percent of cases have been reported in Missouri, Arkansas & Oklahoma.

Dyspareuria

 Dyspareunia can affect all genders, but it is most commonly reported in women. Therefore, this article focuses on dyspareunia in women.

Red flag symptoms

• Dysmenorrhoea
• Intermenstrual bleeding
• Menorrhagia
• Pelvic discharge
• Pelvic pain
• Postcoital bleeding
• Unintentional weight loss
• Fever

Classification

Dyspareunia can be classified as primary or secondary, and as superficial or deep.

• Primary: pain on intercourse since the onset of sexual activity.
• Secondary: development of pain during a patient's sexual lifetime.
• Superficial: symptoms are localised to the introitus, vulva, and vestibule.
• Deep: symptoms relate to the pelvis.

History

There are many causes of dyspareunia. A complete gynaecological history, including sexual history and any history of abuse, is imperative. Although a pelvic examination can be a key element of the work-up, it may not always be necessary.

The consultation may be difficult and clinicians need to be sensitive to the patient in broaching this subject. Creating a rapport with the patient by using open-ended questions may help communication.

Of note, dyspareunia may not be a presenting symptom and may be revealed in response to a screen in a person presenting with other gynaecological symptoms (for example, inter-menstrual bleeding or post-coital bleeding).

The main things to establish in the history are the onset and location of symptoms and any associated complaints.

• Associated pruritus may indicate eczema, candidiasis, or vulvar dystrophy.
• Dysmenorrhoea and sharp pains may indicate endometriosis.
• Pelvic aching may suggest fibroids, and tearing pains may allude to vaginal atrophy.
• A past medical history of cancer that required chemotherapy or radiotherapy may have resulted in vaginal atrophy, fibrosis or adhesions.
• Drugs, such as the contraceptive pill, some antidepressants and antihypertensives, can reduce vaginal lubrication.
• A past obstetric history of traumatic childbirth, or episiotomies, may result in dyspareunia.
• A detailed sexual history may be relevant.
• Any psychological trauma may be very relevant. For example, experiencing sexual assault or abuse. 

Examination

Examination should begin with inspection of the external genitalia. Look out for any dermatological abnormalities or infective lesions, such as herpes simplex virus sores. Pale vaginal mucosa may suggest vaginal atrophy, and candidiasis may also be very obvious on examination.

Depending on the history, an internal exam should also be considered. Mucopurulent discharge may suggest cervicitis or pelvic inflammatory disease. Bimanual examination may show fibroids. Other important features on examination may be a degree of prolapse.

Pale vaginal mucosa may suggest vaginal atrophy.

Investigations

In many cases of dyspareunia, investigations are not necessary. However,  you may wish to consider vaginal swabs for chlamydia and gonorrhoea if pelvic inflammatory disease is suspected. Herpes simplex virus polymerase chain reaction (PCR) swabs may also be pertinent. Other potential investigations are listed below.

• A urinalysis may reveal a urinary tract infection.
• A pelvic ultrasound can be useful to show fibroids or a hydrosalpinx.
• A cystoscopy may be necessary to identify interstitial cystitis.
• A diagnostic laparoscopy may be relevant for suspected endometriosis.

Possible causes of dyspareunia

• Bartholin's cyst
• Cervicitis
• Endometriosis
• Herpes simplex virus
• Iatrogenic causes
• Irritable bowel syndrome
• Inflammatory bowel disease (occasionally)
• Ovarian cysts
• Pelvic inflammatory disease
• Psychosexual syndrome
• Vaginal atrophy (secondary to menopause)
• Vaginismus
• Vaginitis and vulvovaginitis
• Vulvodynia

This article was updated by Dr Pipin Singh, a GP in Northumberland in February 2024. It was written originally by Dr Mehul Mathukia and updated in June 2020 by Dr Anish Kotecha a GP in Gwent.

Gastric Mucosa Barrier

Tardive Dyskinesia

•  Tardive dyskinesias (TDs) are involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated with long-term dopaminergic antagonist medications.
• Although they are associated with the use of neuroleptics, TDs apparently existed before the development of these agents.
• People with schizophrenia and other neuropsychiatric disorders are especially vulnerable to te development of TDs after exposure to conventional neuroleptics, anticholinergics, toxins, substances of abuse, and other agents.
• TDs are most common in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who have been treated with antipsychotic medication for long periods, but they occasionally occur in other patients as well. For example, people with fetal syndrome, other developmental disabilities, and other brain disorders are vulnerable to the development of TDs,  even after receiving only 1 dose of the causative agent.
• TD has been associated with polymorphisms of  both the dopamine receptor D2 (DRD2) gene, 

TD has been associated with polymorphisms of both the dopamine receptor D2 (DRD2) gene, ^[1]  TaqI A and TaqI B and associated haplotypes, ^[2]  and of the dopamine receptor D3 (DRD3) gene, ^[1, 3]  the dopamine transporter (DAT) gene, and the manganese superoxide dismutase (MnSOD) gene.

Dysfunction of the dopamine transporter has been hypothesized to play a role in the development of TD. However, Lafuente et al did not find evidence of involvement of a polymorphism with a variable number of tandem repeats (VNTD) in the DAT gene (SLC6A3) in dyskinesias induced by antipsychotics. ^[4] Thus, further research is needed to investigate the role of the dopamine transporter in the development and maintenance of TD.

Morphine

•  FDA-approved usage of morphine sulfate includes moderate to severe pain that may be acute or chronic.
• Most commonly used in pain management, morphine provides major relief to patients afflicted with pain.
• Clinical situations that benefit greatly from medicating with morphine include management of palliative/end-of-life care, active cancer treatment, and vase-occlusive pain during a sickle cell crisis.
• Morphine is widely used off-label for almost any condition that causes pain.
• In the emergency department, morphine is given for musculoskeletal pain, chest pain, arthritis, and even headaches when patients fail to respond to first and second-line agents. 
• Morphine is rarely used for procedural sedation. However, for small procedures, physicians will sometimes combine a low dose of morphine with a low dose of benzodiazepine-like lorazepam.
• Patients who are actively having acute coronary syndrome are often given morphine in the emergency setting before going to the cath lab.
• Morphine to relieve pain during a myocardial infarction (MI) has been in use since the early 1900s. 
• In 2005, an observational study raised some concerns, but there are very few effective alternatives.
• Morphine is a potent opioid; it decreases pain, which in turn leads to a decrease in the activation of the autonomic nervous system.
• These are desirable effects when a patient is having an Ml. 
• Morphine has hemodynamic side effects that can be beneficial during an MI.   
• In theory, the combination of these can reduce myocardial oxygen demand.     
• Mechanism of Action: 
• Morphine is considered the classic opioid analgesic with which other painkillers are compared.
• Like other medications in this class, morphine has an affinity for delta, Kappa and mu-opioid receptors. 
• This drug produces most of its analgesic effects by binding to the mu-opioid receptor within the central nervous system (CNS) and the peripheral nervous system (PNS). 
• The net effect of morphine is the activation of descending inhibitory pathways of the CNS as well as inhibition of the nociceptive afferent neurons of the PNS, which leads to an overall reduction of nociceptive transmission.
• Administration:         
• Morphine administration can occur through various vehicles. Its administration is most often via the following routes: orally (PO), intravenously (IV), epidural, and intrathecal. 
• Oral formulations are available in both immediate and extended-release for the treatment of acute and chronic pain.
• Pain that is more severe and not well controlled may be manageable with single or continuous doses of IV, epidural, and intrathecal formulations. 
• Infusion dosing can vary significantly between patients and largely depends on how naive or tolerant they are to opiates. 
• It is interesting to point out that IV morphine formulation is also commonly given intramuscularly (IM). 
• Morphine is also available as a suppository. 
• Morphine is widely used and abused. As a result of this, people have found ways to insufflate (snort) the medication.
• Morphine is also available as an oral solution and can be administered sublingually.
• Sublingual morphine is very popular in palliative care.
• Adverse Effects
• Among the more common unwanted effects of morphine use is constipation. This effect occurs via stimulation of mu-opioid receptors on the myenteric plexus, which in turn inhibits gastric emptying and reduces peristalsis.
• Other common side effects include central nervous system depression, nausea, vomiting and urinary retention. 
• Respiratory depression is among the more serious adverse reactions with opiate use that is especially important to monitor in the postoperative patient population.
• Other reported side effects include lightheadedness, sedation, and dizziness.
• Patients often report nausea and vomiting, which is why in many emergency departments, morphine administration is with an antiemetic such as ondansetron.
• Other effects include euphoria, dysphoria, agitation, dry mouth, anorexia, and biliary tract spasm. which is why some physicians will avoid morphine when patients present with right upper quadrant pain and they suspect possible biliary tract pathology.
• Morphine can also affect the cardiovascular system and reportedly can cause flushing, bradycardia, hypotension, and syncope.
• It is also important to note that patients can experience pruritus, urticaria, edema and other skin rashes.
• Contraindications
• Morphine is an extremely beneficial medication when used appropriately. However, in certain situations, this medication may be strongly contraindicated. Extreme caution is necessary with severe respiratory depression and asthma exacerbation cases since morphine can further decrease the respiratory drive. Additionally, morphine should be avoided in cases of previous hypersensitivity reaction and immediately discontinued in the presence of an active reaction.[11] Caution is also necessary with the concurrent use of monoamine oxidase inhibitors (MAOIs) as these medications have an additive effect with morphine. This combination can then trigger severe hypotension, serotonin syndrome, or increase respiratory depression in patients. GI obstruction is another important contraindication.[1] It is also considered by many as a contraindication to provide opioids to individuals that have a history of substance misuse, especially if a patient has had a history of abusing opioids. Although this is a very controversial topic, most clinicians would agree that pain requires management.[12] However, most will agree and acknowledge that there are alternatives to opioid analgesics.
• Monitoring
• The efficacy and therapeutic index of morphine are assessable with a combination of subjective and objective findings. Controlling pain, which is usually the first symptom evaluated in patients, is the ultimate goal of morphine use. Other essential parameters requiring monitoring include mental status, blood pressure, respiratory drive, and misuse/overuse.[2] Although it may seem intuitive, it is also important to monitor what other medications a patient is taking. This list includes but is not limited to prescription medications. All patients taking morphine should understand the need to avoid any other substances that could lead to respiratory depression.[13] These medications include but are not limited to alcohol, additional opioids, benzodiazepines, and barbiturates. Patients can become apneic at lower doses if combining morphine with any of these substances.
• Toxicity
• Morphine can potentially be a lethal medication when not used properly.[14] It causes a host of symptoms related to depression of the CNS. Severe respiratory depression is the most feared complication of morphine in cases of overdose. Immediate injection of naloxone is required to reverse the effects of morphine.
• Enhancing healthcare Team outcomes

• Ordering and administering morphine requires an interprofessional team of healthcare professionals, including clinicians, mid-level practitioners, nurses, and pharmacists.[15] However, patients may be transferred throughout the hospital while under the effects of these medications. Morphine use, monitoring, and administration can utilize many resources, including laboratory technologists, pharmacists, and nurses/nursing assistants. Without proper training and careful monitoring, often starting in the emergency department, patients can develop serious side effects and have adverse reactions to morphine. The clinician is responsible for coordinating the care, which includes the following:

  • Ordering the drug
  • Monitoring the patient for signs and symptoms of respiratory depression[16]
  • Administering the drug
  • Consulting with the pharmacist about the use of morphine with other medications that can cause respiratory depression.
  • Consulting with a specialist if an overdose or allergic reaction occurs.
  • Consulting with the radiology if a patient has received morphine prior to imaging
  • consulting with the cardiologist if using morphine in a STEMI                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 

Antipsychotic Drugs and Liver Injury

•  Drug-induced liver injury (DILI) refers to liver injury caused by various prescription or non-prescription chemical drugs, biological agents, traditional Chinese medicine (TCM), natural medicine (NM), health care products (HP), dietary supplements (DS), and their metabolites and even excipients.
• It was reported that DILI accounted for 10-15% of adverse drug effects.
• Among the main drugs causing DILI in our country, sedatives, and neuropsychiatric drugs accounted for 2.6%.
• Systematic reviews have found that all patients treated with conventional antipsychotic therapy have an increased risk of hepatic dysfunction.
• The risk factors for DILI were host factors (including genetic factors, age, gender, pregnancy, and underlying disease), drug factors (including chemical properties of drugs, interactions, and pollution in the course of planting and processing the traditional Chinese medicinal materials) and environmental factors (excessive drinking and smoking, etc.)
• The pathogenesis of DILI is complicated, and it is often the result of successive or combined effects of various mechanisms that still need to be fully clarified.
• The clinical manifestations were mostly asymptomatic transaminase elevation and it happened in the initial 6 weeks of using antipsychotic drugs.
• Abnormal liver function can be stabilized or improved via treatments and fatal hepatitis rarely happens. 
• It is necessary to point out that chlorpromazine often triggers cholestatic liver injury. This injury is generally regarded as a relatively severe liver injury.
• DILI has a complex pathogenesis that can be summarized into direct hepatotoxicity and idiosyncratic hepatotoxicity reactions to drugs.
• The process involves the upstream events caused by drugs and their metabolites, and the downstream events constituted by the imbalances in hepatic target cell damage pathways and protective pathways. 
• Direct hepatotoxicity of drugs refers to the drugs ingested into the body and/or the direct damage of its metabolites to the liver and was often dose-dependent, usually predictable, and also called intrinsic DILI.
• Direct hepatotoxicity of drugs can further induce other liver injury mechanisms such as immunity and inflammatory response.
• The pathogenesis of idiosyncratic hepatotoxicity has been a hot topic in research in recent years. 
• Gene polymorphisms of the drug-metabolizing enzymes, transmembrane transporters and solute transport proteins, and human leukocyte antigen systems (HLA) result in adaptive immune responses to some drugs relatively easily, increasing the host's susceptibility to DILI.
• Hepatic mitochondrial damage and oxidative stress induced by drugs and active metabolites can cause hepatocyte damage and death through various molecular mechanisms. 
• Persistent and excessive endoplasmic reticulum stress response (ERSR) broke the alleviating effect of the unfolded protein response (UPR) on stress, facilitating the progress of DILI. 
• Drugs and their metabolites are capable of activating a variety of death signaling pathways, promoting the occurrence of cell necrosis and autophagic cell death.
• The adaptive immune attack may be the last common event of DILI.
• Most antipsychotic drugs (except sulpiride, amisulpride, risperidone, and paliperidone) are metabolized through the cytochrome P450 (CYP) system. 
• The majority of antipsychotic drugs mainly metabolize through CYP2D6 and CYP3A4 and some antipsychotic drugs are through CYP1A2 (such as clozapine and olanzapine).
• There may be three main mechanisms underlying the hepatic injury induced by antipsychotic drugs: 
• firstly, phenothiazines (especially chlorpromazine) or their metabolites can affect bile secretion, and excretion, resulting in cholestasis which may be related to immune-mediated hypersensitivity.
• Secondly, the direct toxic effects of the drugs or their metabolites attack hepatocytes; the delayed toxic effect is caused by a gradual accumulation of small toxic metabolites. Although the drug continues to damage the hepatocytes, the hepatocyte can adapt to this change by up-regulation of antioxidant genes or chaperone proteins. 
• Thirdly, antipsychotic drugs indirectly affect the liver by increasing the risk of metabolic syndrome, leading to an increased risk of non-alcoholic fatty liver disease. Some studies have found that clozapine and olanzapine increase the risk of non-alcoholic fatty liver disease compared with other novel antipsychotic drugs and there were 2 case reports regarding acute liver damage after using clozapine.
• Clozapine, olanzapine, quetiapine and risperidone resulted in 40%, 30%, 27% and 31% of asymptomatic elevation of aminotransferase respectively.
• Generally, it takes place in the first few days to weeks of taking the mediction. The target cells of DILI are mainly the hepatic cells, bile duct epithelial cells, and vascular endothelial cells in the hepatic sinusoid and hepatic vein system. The injury modes are complex and diverse; the pathological changes cover almost all the areas of liver pathological changes. Most of the pathological changes caused by antipsychotics are mainly in the form of acute cellular lysis.[14] The hepatotoxicity induced by conventional antipsychotic drugs is represented by phenothiazine. Especially liver injury caused by chlorpromazine is manifested as acute cholestasis. The hepatic injury modes of the novel antipsychotics are diverse. Studies[14] have shown that clozapine can cause acute necrotic hepatitis, cholestatic hepatitis with necrosis of a single hepatocyte, and eosinophil infiltration; risperidone usually results in cholestatic hepatitis and rare allergic symptoms; olanzapine induces hepatocyte damage, accompanied monocytes, centrolobular necrosis of lymphocytes, and eosinophils infiltration in the portal area; quetiapine is the leading cause of hepatocyte damage, extensive necrosis of hepatocytes, and nonspecific inflammatory infiltration; ziprasidone usually causes hepatocyte damage, hypersensitivity, eosinophilic and systemic symptoms drug-induced reaction syndrome; aripiprazole, paliperidone, aripiprazole, amisulpride have no relevant reports.

The clinical manifestations of acute DILI are usually non-specific. The incubation period varies considerably in that it can last as short as one to several days and up to several months. Most patients had no obvious symptoms with only an increase of varying degrees on hepatic biochemical indicators such as serum ALT, AST and ALP, GGT, and so forth. Some patients may have digestive symptoms such as fatigue, loss of appetite, distending pain in the liver area, and epigastric discomfort. People with cholestasis can have yellow skin over the entire body, pale stool color, itching, and so forth. A small number of patients may have allergic reactions such as fever, rash, eosinophilia, and even arthralgia, and possibly be accompanied with manifestations of other extrahepatic organ injuries. Acute liver failure (ALF) or subacute liver failure (SALF) may be present in severe cases. Studies have found that new antipsychotic drugs rarely showed hepatic injury that was accompanied with jaundice in clinical practice, and the cause was unknown.[1] Chronic DILI in clinical practice can be manifested as chronic hepatitis, hepatic fibrosis, compensated and decompensated cirrhosis, autoimmune-like hepatitis (AIH) DILI, chronic cholestasis, vanishing bile duct syndrome (VBDS), and so forth. It is relatively easy for cholestatic DILI to develop into a chronic condition.[15]

The clinical manifestations of acute DILI are usually non-specific. The incubation period varies considerably in that it can last as short as one to several days and up to several months. Most patients had no obvious symptoms with only an increase of varying degrees on hepatic biochemical indicators such as serum ALT, AST and ALP, GGT, and so forth. Some patients may have digestive symptoms such as fatigue, loss of appetite, distending pain in the liver area, and epigastric discomfort. People with cholestasis can have yellow skin over the entire body, pale stool color, itching, and so forth. A small number of patients may have allergic reactions such as fever, rash, eosinophilia, and even arthralgia, and possibly be accompanied with manifestations of other extrahepatic organ injuries. Acute liver failure (ALF) or subacute liver failure (SALF) may be present in severe cases. Studies have found that new antipsychotic drugs rarely showed hepatic injury that was accompanied with jaundice in clinical practice, and the cause was unknown.[1] Chronic DILI in clinical practice can be manifested as chronic hepatitis, hepatic fibrosis, compensated and decompensated cirrhosis, autoimmune-like hepatitis (AIH) DILI, chronic cholestasis, vanishing bile duct syndrome (VBDS), and so forth. It is relatively easy for cholestatic DILI to develop into a chronic condition.[15]

The severity of DILI was graded according to clinical features and laboratory indexes ALT, ALP, TBil, and INR (international normalized ratio). It is divided into 5 grades, including no liver injury, mild, moderate and severe liver injuries, ALF, and faAt present, the diagnostic criteria commonly used for drug-induced liver injury (DILI) in the world are: the Japanese Diagnostic Criteria for Drug-induced Liver Injury developed by the Japanese Liver and Drug Research Society in 1978; the European Consensus Meeting Criteria for Acute Drug-induced Liver Injury developed by Danan and colleagues in 1988; the ICM standard developed by the Council for International Organization of Medical Sciences (CIOMS) in 1993 (this had improvements to the Danan standards); the Maria Diagnositc Criteria developed by Maria in 1997; the DDW Japan criteria developed by the Japanese Society of Hepatology in 2004. In our country, the most commonly used set of criteria was the one that used medical history, symptoms, and signs combined with laboratory markers as the diagnostic criteria for DILI.[16]

The clinical manifestations and histological features of drug-induced liver injury were similar to most types of liver diseases, and the same drug can present different characteristics (including clinical features, pathological manifestation, and latency manifestation). Additionally, the diagnosis of DILI is not convincing enough at present due to the lack of specific biological indicators (laboratory, radiological, imaging or histological manifestations).[14] Therefore, some studies[14] have proposed a train of thought for diagnosis: 1) establishing diagnostic procedures: there is a need for understanding comprehensively the relationship between patients’ medication use situation and liver injury in clinical practice, awareness of the risk of liver injury caused by drugs, knowing the liver injury risk caused by drugs, and excluding other factors that could lead to liver injury (for example, viruses, infections, autoimmune diseases, and ischemic and metabolic diseases). 2) Observing the clinical manifestations and evaluating risk factors: acute and chronic liver injuries can have all kinds of clinical manifestations, mainly in the form of acute cytolysis; hepatocellular injury, being female, high total bilirubin, high AST, and AST/ALT > 1.5 are the risk factors for developing acute liver injury. 3) Evaluating the biochemical markers of liver at baseline: weight gain and metabolic syndrome caused by new antipsychotic drugs impair the liver function indirectly. Therefore, it is necessary to define the type of liver injury and, more importantly, to record the patients’ liver and other metabolic markers before taking medication. 4) Age: age can determine the biochemical expression of hepatotoxicity. Elderly patients have a strong relationship with cholestatic or mixed liver injury. It is more common to express as hepatocellular toxicity in young patients. 5) Comorbidity and concomitant medication: psychiatric patients have more comorbidity and concomitant medication situations. The past history, medication history, including the use of traditional Chinese medicine and dietary supplements of this kind of patients should be known. In addition, it should be noted that the recent use of drugs does not necessarily mean it is relevant to liver injury.

According to the preliminarily established and posteriorly revised DILI classification criteria by the Council for International Organization of Medical Sciences (CIOMS), DILI was classified into 3 types: liver cell type, intrahepatic cholestasis type and mixed type. Liver cell type: ALT≥ 3 normal upper limit (ULN), and R≥ 5 [R= (ALT measured value/ ALT ULN) / (ALP measured value/ ALP ULN)]; cholestatic type: ALP≥ 2 ULN, and R≤ 2; mixed type: ALT≥ 3 ULN, ALP≥ 2 ULN, and 2< R<5. If ALT and ALP do not meet the above criteria, they are called the abnormal liver biochemical test. The cholestatic type DILI accounts for approximately 30% of DILI.

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5. Clinical management strategy

The basic treatment principle of DILI is: 1) stop using the suspected liver injury drugs promptly and try to avoid using suspicious or similar drugs again; 2) one should weigh the progression of primary diseases after stopping medication and the risk of aggravating liver injury caused by continuous use of medication; 3) choosing appropriate medication treatment according to the clinical type of DILI; 4) patients with acute liver failure / subacute liver failure can consider emergency liver transplantation when necessary.

Currently, there is no clear guideline for the impairment of liver function caused by antipsychotic drugs in clinical practice and it is still based on clinical recommendations, or guidelines from various centers. A more consistent suggestion is that liver function tests should be performed prior to the use of antipsychotic drugs,[17] to understand the patient’s baseline period status. Once liver function impairment is found in the baseline period, it is recommended to use antipsychotic medication that has low doses or metabolize less through livers (for instance, sulpiride, amisulpride, and paliperidone). Patients with liver injury should avoid using phenothiazines. Some common adverse drug reactions (such as excessive sedation or constipation) can also aggravate the impairment of liver function. For those who had liver injury before the use of antipsychotic drugs, liver function tests should be performed at least once a week in the early stage.[18] If the patient has normal liver function at baseline, regular liver function tests are needed even after using antipsychotic medication.[18] It is recommended to have the exam at least once a year (patients who take clozapine have the test every six months). Some centers believe that liver function should be evaluated frequently (usually every three months) during the first year of using antipsychotic drugs (especially with patients with alcohol or drug use). Patients with clinical symptoms, (such as jaundice, nausea, vomiting, anorexia, weakness, pale urine, or black stool) should increase the number of liver function tests. Once the patient was found to be suffering from liver damage due to the use of antipsychotic drugs (ALT≥ 3 times ULN or ALP≥ 2 times ULN or TB> 2mg/dl), it is suggested to stop the medication treatment as soon as possible[8] receive liver-protecting treatment, or get a referral to a general hospital. If mild and asymptomatic liver injuries occur and they do not meet the above criteria, whether there is alcohol or substance use should be assessed including other possible risk factors. Clinical observation should be strengthened without the discontinuation of antipsychotic drugs.[8] If patients suffer from transient liver damage that mostly had a low correlation with antipsychotic drugs, clinical and laboratory monitoring can be strengthened without discontinuation of antipsychotic drugs.[8]

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6. Conclusions

The mechanism of liver injury induced by antipsychotic drugs is different. The liver injuries induced by typical antipsychotic drugs that represented by chlorpromazine are mostly presented as cholestasis type. Novel antipsychotics primarily cause liver injury indirectly through adverse events associated with metabolism (weight gain, obesity, metabolic syndrome, etc.). Liver function monitoring is still necessary before and after treatment. It is necessary to continue the promotion of clinical and basic research on DILI induced by antipsychotic medication in the future, including applied genomics, transcriptomics, proteomics, metabonomics and other “omics” techniques assessing the incidence of DILI before and after onset and genetics between individuals, as well as studies of immunology, molecular biology, the change of biochemistry and such events, conducting big data analysis, and promoting the study of pathogenesis. These will all serve to identify patients’ susceptibility, adaptability, and tolerance to specific antipsychotic drugs in the early stage, thereby improving prevention of DILI.tal [4]

Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction

 Most trials that have shown a benefit of beta-blocker treatment after myocardial infarction included patients with large myocardial infarctions and were conducted in an era before modern biomarker-based diagnosis of myocardial infarction and treatment with percutaneous coronary intervention, antithrombotic agents, high-intensity statins, and renin–angiotensin–aldosterone system antagonists.

CONCLUSIONS

Among patients with acute myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction (≥50%), long-term beta-blocker treatment did not lead to a lower risk of the composite primary end point of death from any cause or new myocardial infarction than no beta-blocker use. (Funded by the Swedish Research Council and others; REDUCE-AMI ClinicalTrials.gov number, NCT03278509.)

The efficacy of beta-blockers in patients with heart failure and reduced ejection fraction is well documented. Trials have also shown that long-term beta-blocker therapy after myocardial infarction reduces mortality by approximately 20%.1-3 However, these results are from trials that mainly involved patients with large myocardial infarctions and left ventricular systolic dysfunction and were conducted primarily in the 1980s. This era predates advancements such as high-sensitivity cardiac troponins, percutaneous coronary interventions, antithrombotic agents, high-intensity statins, and renin–angiotensin–aldosterone system antagonists. A meta-analysis suggested that in the era of modern reperfusion strategies, beta-blockers did not significantly reduce mortality.4 Data on the effect of long-term beta-blocker therapy in patients with acute myocardial infarction and preserved ejection fraction are lacking from contemporary, sufficiently powered, randomized clinical trials.

Divergent conclusions have emerged from extensive observational studies and meta-analyses of such studies.5-10 A Cochrane review underscored the need for new trials in this patient population to address current clinical practices.11 Despite the lack of clear evidence of benefit in the contemporary setting, current guidelines widely recommend beta-blocker use after myocardial infarction.12-14 We conducted a trial (Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction [REDUCE-AMI]) to investigate whether long-term oral beta-blocker treatment in patients with acute myocardial infarction and preserved left ventricular ejection fraction would lead to a lower risk of a composite end point of death of any cause or new myocardial infarction than no beta-blocker use.

Discussion

In this registry-based, prospective, randomized, open-label, parallel-group trial conducted across 45 centers, most of which were in Sweden, the early initiation of oral beta-blocker treatment after an acute myocardial infarction in patients with a preserved left ventricular ejection fraction did not lead to a lower cumulative incidence of death from any cause or new myocardial infarction (composite primary end point). In addition, no appreciable between-group differences were observed in the analyses of secondary efficacy and safety end points. After 1 year, the incidence and severity of symptoms appeared to be similar in the two groups among the patients in Sweden who attended registry follow-up visits and had symptoms assessed. The absence of an effect of beta-blocker treatment on the cumulative incidence of death or myocardial infarction appeared to be consistent across all prespecified subgroups.

The baseline characteristics indicated that the patients who were included in the trial were representative of the population of patients with myocardial infarction and preserved ejection fraction in the trial countries (Table S6) and were generally at low risk for new cardiac events. The patients were well treated with early revascularization procedures and received evidence-based medications at discharge. The overall annual event rates for the primary end point (2.4% in the beta-blocker group and 2.5% in the no–beta-blocker group) were lower than we had expected before the initiation of the trial. We designed the trial as a superiority trial, powered to detect a 25% lower risk of death or myocardial infarction with beta-blocker treatment (corresponding to a 0.7-percentage-point lower risk per year, given the actual annual event rates that we observed), which we regarded as a clinically relevant effect. Although the neutral result that we found in this trial does not rule out either a small beneficial or detrimental effect, the overlapping time-to-event curves that were observed throughout the follow-up period and the consistent results in all the prespecified subgroups and for the secondary end points make a clinically relevant difference unlikely. Our findings are also consistent with the results of several large observational studies and meta-analyses of such studies.5,7,9,10 The possible signal of a harmful effect of beta-blocker treatment in the subgroup of patients who were taking a beta-blocker at admission is of unclear relevance and is probably a spurious finding.

Our trial included only patients who had a left ventricular ejection fraction of at least 50%. During the planning phase, many potential investigators were hesitant to include patients who had a mid-range left ventricular ejection fraction (40 to 49%). We also wanted to keep the trial population as homogeneous as possible, since any interaction between trial group and a subgroup makes the trial results more difficult to interpret and generalize. A later meta-analysis of clinical trials involving patients with a mid-range left ventricular ejection fraction suggested a beneficial effect of beta-blockers generally, and a large Korean registry suggested a benefit specifically after myocardial infarction.7,17

We allowed only beta-1–receptor selective blockers (metoprolol and bisoprolol) because these drugs had the best documentation for long-term treatment and had been used extensively in the countries involved in the trial. Indications for beta-blockers other than secondary prevention was an exclusion criterion. We also mandated an early invasive strategy because it reflects a contemporary treatment strategy — that is, the basis for reevaluation of beta-blockers in a new trial. Three other large, ongoing trials examining long-term treatment with beta-blockers in patients with myocardial infarction and preserved fraction have defined a preserved ejection fraction of at least 40% and also are allowing the use of nonselective beta-blockers.18-20 Two of the trials also include patients being treated without an early invasive approach.18,19

The doses of beta-blockers that were used in our trial were lower than those in previous trials. However, the doses that were used in our trial mirror the current practice of beta-blocker treatment, and no apparent association between the planned target dose of beta-blocker treatment and the primary end point was observed. Results from contemporary observational studies comparing various doses of beta-blockers have not shown any clear association with outcome.21,22 A study from the SWEDEHEART registry that compared 33,126 patients who received a prescription for at least 50% of the target beta-blocker dose at discharge with 64,449 patients who received a prescription for less than 50% of that dose did not show a between-group difference in outcome.22

Our trial has several limitations. First, it was an open-label trial, because blinding was not judged to be feasible. Data on clinical end points were obtained from the SWEDEHEART registry and the Swedish Population Registry and were not centrally adjudicated. However, this approach should have had a limited effect on the hard composite primary end point, whereas results regarding softer end points such as symptoms need to be interpreted more cautiously. During follow-up, investigators reviewed electronic health records to confirm that reported new myocardial infarctions in the SWEDEHEART registry fulfilled the criteria for a myocardial infarction according to the treating physician, and any misclassification should have been equally distributed over the two randomized trial groups.

Second, only safety end points that are associated with hospitalization were assessed. Third, a limitation of pragmatic trials of routinely used therapy is the potential for crossovers. Despite strategies to mitigate this issue, among patients with available information, 14% of those who had been assigned to the no–beta-blocker group were taking beta-blockers after 1 year of follow-up, and we do not yet have information about beta-blocker use after the first year. The adherence to the assigned beta-blocker regimen mirrored patterns that are observed in everyday clinical practice23,24; however, we cannot rule out the possibility that the use of beta blockers in the no–beta-blocker group contributed to our null finding.

In this registry-based, prospective, randomized, open-label, parallel-group trial that investigated whether oral beta-blocker therapy that was initiated early in patients with myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction would improve long-term outcome, beta-blocker treatment did not result in a lower cumulative incidence of the composite primary end point of death from any cause or new myocardial infarction.