<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Organophosphate poisoning and explain in detail? [/INST] Organophosphate poisoning is poisoning due to organophosphates (OPs). Organophosphates are used as insecticides, medications, and nerve agents. Symptoms include increased saliva and tear production, diarrhea, vomiting, small pupils, sweating, muscle tremors, and confusion. While onset of symptoms is often within minutes to hours, some symptoms can take weeks to appear. Symptoms can last for days to weeks.Organophosphate poisoning occurs most commonly as a suicide attempt in farming areas of the developing world and less commonly by accident. Exposure can be from drinking, breathing in the vapors, or skin exposure. The underlying mechanism involves the inhibition of acetylcholinesterase (AChE), leading to the buildup of acetylcholine (ACh) in the body. Diagnosis is typically based on the symptoms and can be confirmed by measuring butyrylcholinesterase activity in the blood. Carbamate poisoning can present similarly.Prevention efforts include banning very toxic types of organophosphates. Among those who work with pesticides the use of protective clothing and showering before going home is also useful. In those who have organophosphate poisoning the primary treatments are atropine, oximes such as pralidoxime, and diazepam. General measures such as oxygen and intravenous fluids are also recommended. Attempts to decontaminate the stomach, with activated charcoal or other means, have not been shown to be useful. While there is a theoretical risk of health care workers taking care of a poisoned person becoming poisoned themselves, the degree of risk appears to be very small.OPs are one of the most common causes of poisoning worldwide. There are nearly 3 million poisonings per year resulting in two hundred thousand deaths. Around 15% of people who are poisoned die as a result. Organophosphate poisoning has been reported at least since 1962.

Signs and symptoms
The symptoms of organophosphate poisoning include muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis. Other symptoms include hypertension, and hypoglycemia.
Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur.The effects of organophosphate poisoning on muscarinic receptors are recalled using the mnemonic SLUDGEM (salivation, lacrimation, urination, defecation, gastrointestinal motility, emesis, miosis) An additional mnemonic is MUDDLES: miosis, urination, diarrhea, diaphoresis, lacrimation, excitation, and salivation.The onset and severity of symptoms, whether acute or chronic, depends upon the specific chemical, the route of exposure (skin, lungs, or GI tract), the dose, and the individuals ability to degrade the compound, which the PON1 enzyme level will affect.

Reproductive effects
Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to OP pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticides in rural areas. For those males exposed to OP pesticides, poor semen and sperm quality have been seen, including reduced seminal volume and percentage motility, as well as a decrease in sperm count per ejaculate. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to OP pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. The effects of OP exposure on infants and children are at this time currently being researched to come to a conclusive finding.
Evidence of OP exposure in pregnant mothers are linked to several health effects in the fetus. Some of these effects include delayed mental development, Pervasive developmental disorder (PDD), morphological abnormalities in the cerebral surface.

Neurotoxic effects
Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
Cholinergic syndrome occurs in acute poisonings with OP pesticides and is directly related to levels of AChE activity. Symptoms include miosis, sweating, lacrimation, gastrointestinal symptoms, respiratory difficulties, shortness of breath, slowed heart rate, cyanosis, vomiting, diarrhea, trouble sleeping, as well as other symptoms. Along with these central effects can be seen and finally seizures, convulsions, coma, respiratory failure. If the person survives the first day of poisoning, personality changes can occur, in addition to aggressive behavior, psychotic episodes, memory and attention disturbances, and other delayed effects. When death occurs, it is most commonly due to respiratory failure due to paralysis of respiratory muscles and depression of central nervous system, which is responsible for respiration. For people affected by cholinergic syndrome, atropine sulfate combined with an oxime is used to combat the effects of the acute OP poisoning. Diazepam is sometimes also administered.The intermediate syndrome (IMS) appears in the interval between the end of the cholinergic crisis and the onset of OPIDP. Symptoms associated with IMS manifest between 24 and 96 hours after exposure. The exact etiology, incidence, and risk factors associated with IMS are not well understood, but IMS is recognized as a disorder of neuromuscular junctions. IMS occurs when a person has a prolonged and severe inhibition of AChE. It has been linked to specific OP pesticides such as parathion, methylparathion, and dichlorvos. Patients generally present with increasing weakness in the facial, neck flexor, and respiratory muscles.
OPIDP occurs in a small percentage of cases, roughly two weeks after exposure, where temporary paralysis occurs. This loss of function and ataxia of peripheral nerves and spinal cord is the phenomenon of OPIDP. Once the symptoms begin with shooting pains in both legs, the symptoms continue to worsen for 3–6 months. In the most severe cases quadriplegia has been observed. Treatment only affects sensory nerves, not motor neurons which may permanently lose function. The aging and phosphorylation of more than 70% of functional NTE in peripheral nerves is one of the processes involved in OPIDP.  Standard treatments for OP poisoning are ineffective for OPIDP.
COPIND occurs without cholinergic symptoms and is independent of AChE inhibition. COPIND appears with a delay and is long lasting. Symptoms associated with COPIND include cognitive deficit, mood changes, autonomic dysfunction, peripheral neuropathy, and extrapyramidal symptoms. The underlying mechanisms of COPIND have not been determined, but it is hypothesized that withdrawal of OP pesticides after chronic exposure or acute exposure could be a factor.

Pregnancy
Evidence of exposure to OP pesticides during gestation and early postnatal period have been linked to neurodevelopmental effects in animals, specifically rats. Animals exposed in utero to chlorpyrifos exhibited decreased balance, poorer cliff avoidance, decreased locomotion, delays in maze performance, and increased gait abnormalities. Early gestation is believed to be a critical time period for the neurodevelopmental effects of pesticides. OPs affect the cholinergic system of fetuses, so exposure to chlorpyrifos during critical periods of brain development potentially could cause cellular, synaptic, and neurobehavioral abnormalities in animals. In rats exposed to methylparathion, studies found reduced AChE activity in all brain regions and subtle alterations in behaviors such as locomotor activity and impaired cage emergence. Organophosphates as whole have been linked to decreases in the length of limbs, head circumference, and slower rates of postnatal weight gain in mice.

Cancer
The International Agency for Research on Cancer (IARC) found that organophosphate exposure may increase cancer risk. Tetrachlorvinphos and parathion were classified as "possibly carcinogenic", malathion, and diazinon.

Cause
OP pesticide exposure occurs through inhalation, ingestion and dermal contact. Because OP pesticides degrade quickly when exposed to air and light, they have been considered relatively safe to consumers. However, OP residues may linger on fruits and vegetables. Certain OP pesticides have been banned for use on some crops, For example, methyl parathion is banned from use on some crops and permitted on others. It can also occur through deliberate poisoning using nerve agents such as sarin and tabun.

Examples
Insecticides including malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos, ethion, trichlorfon
Nerve agents including soman, sarin, tabun, VX
Herbicides including tribufos [DEF], merphos are tricresyl phosphate–containing industrial chemicals.Exposure to any of the above-listed organophosphates may occur through inhalation, skin absorption, and ingestion, most commonly of food that has been treated with an OP herbicide or insecticide. Exposure to these chemicals can occur at public buildings, schools, residential areas, and in agricultural areas. Chlorpyrifos and Malathion have been linked to reproductive effects, neurotoxicity, kidney/liver damage, and birth defects. Dichlorvos has also been linked to reproductive effects, neurotoxicity, and kidney/liver damage. It is also recognized to be a possible carcinogen.

Pathophysiology
The health effects associated with organophosphate poisoning are a result of excess acetylcholine (ACh) present at different nerves and receptors in the body because acetylcholinesterase is blocked. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When there is an accumulation of ACh at autonomic ganglia synapses this causes overstimulation of muscarinic expression in the parasympathetic nervous system.
Organophosphates irreversibly and non-competitively inhibit acetylcholinesterase, causing poisoning by phosphorylating the serine hydroxyl residue on AChE, which inactivates AChE. AChE is critical for nerve function, so the inhibition of this enzyme, which causes acetylcholine accumulation, results in muscle overstimulation. This causes disturbances across the cholinergic synapses and can only be reactivated very slowly, if at all. Paraoxonase (PON1) is a key enzyme involved in OP toxicity and has been found to be critical in determining an organisms sensitivity to OP exposure.
PON1 can inactivate some OPs through hydrolysis. PON1 hydrolyzes the active metabolites in several OP insecticides such as chlorpyrifos oxon, and diazoxon, as well as, nerve agents such as soman, sarin, and VX. PON1 hydrolyzes the metabolites, not the parent compounds of insectides. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of OP exposure. Higher levels of PON1 plasma hydrolytic activity provide a greater degree of protection against OP pesticides. Rats injected with purified PON1 from rabbit serum were more resistant to acute cholinergic activity than the control rats. PON1 knockouts in mice are found to be more sensitive to the toxicity of pesticides, like chlorpyrifos. Animal experiments indicate that while PON1 plays a significant role in regulating the toxicity of OPs its degree of protection given depends on the compound (i.e. Chlorpyrifos oxon or diazoxon). The catalytic efficiency with which PON1 can degrade toxic OPs determines the degree of protection that PON1 can provide for organism. The higher the concentration of PON1 the better the protection provided. PON1 activity is much lower in neonates, so neonates are more sensitive to OP exposure. In 2006, reports up to a 13-fold variation was seen in PON1 levels in adults, as well as, specifically regarding sensitivity to diazoxon, a variation up to 26 and 14-fold was reported in a group of newborns and Latino mothers. This wide range in variability of enzyme levels determining a humans sensitivity to various OPs is being researched further.

Diagnosis
A number of measurements exist to assess exposure and early biological effects for organophosphate poisoning. Measurements of OP metabolites in both the blood and urine can be used to determine if a person has been exposed to organophosphates. Specifically in the blood, metabolites of cholinesterases, such as butyrylcholinesterase (BuChE) activity in plasma, neuropathy target esterase (NTE) in lymphocytes, and of acetylcholinesterase (AChE) activity in red blood cells. Due to both AChE and BuChE being the main targets of organophosphates, their measurement is widely used as an indication of an exposure to an OP. The main restriction on this type of diagnosis is that depending on the OP, the degree to which either AChE or BuChE are inhibited differs; therefore, measure of metabolites in blood and urine do not specify which OP agent is responsible for the poisoning. However, for fast initial screening, determining AChE and BuChE activity in the blood are the most widely used procedures for confirming a diagnosis of OP poisoning. The most widely used portable testing device is the Test-mate ChE field test,: 13  which can be used to determine levels of Red Blood Cells (RBC), AChE and plasma (pseudo) cholinesterase (PChE) in the blood in about four minutes.  This test has been shown to be just as effective as a regular laboratory test and because of this, the portable ChE field test is frequently used by people who work with pesticides on a daily basis.

Treatment
Current antidotes for OP poisoning consist of a pretreatment with carbamates to protect AChE from inhibition by OP compounds and post-exposure treatments with anti-cholinergic drugs. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of "-oximes" has been found to be of no benefit, or to be possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally. These antidotes are effective at preventing lethality from OP poisoning, but current treatment lack the ability to prevent post-exposure incapacitation, performance deficits, or permanent brain damage. While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of OP poisoning.Enzyme bioscavengers are being developed as a pretreatment to sequester highly toxic OPs before they can reach their physiological targets and prevent the toxic effects from occurring. Significant advances with cholinesterases (ChEs), specifically human serum BChE (HuBChE) have been made. HuBChe can offer a broad range of protection for nerve agents including soman, sarin, tabun, and VX. HuBChE also possess a very long retention time in the human circulation system and because it is from a human source it will not produce any antagonistic immunological responses. HuBChE is currently being assessed for inclusion into the protective regimen against OP nerve agent poisoning. Currently there is potential for PON1 to be used to treat sarin exposure, but recombinant PON1 variants would need to first be generated to increase its catalytic efficiency.
Another potential treatment being researched is the Class III anti-arrhythmic agents. Hyperkalemia of the tissue is one of the symptoms associated with OP poisoning. While the cellular processes leading to cardiac toxicity are not well understood, the potassium current channels are believed to be involved. Class III anti-arrhythmic agents block the potassium membrane currents in cardiac cells, which makes them a candidate for become a therapeutic of OP poisoning.There is insufficient evidence to support using plasma alkalinisation to treat a person with organophosphate poisoning.

Epidemiology
Organophosphate pesticides are one of the top causes of poisoning worldwide, with an annual incidence of poisonings among agricultural workers varying from 3-10% per country.

History
Ginger Jake
A striking example of OPIDN occurred during the 1930s Prohibition Era when thousands of men in the American South and Midwest developed arm and leg weakness and pain after drinking a "medicinal" alcohol substitute. The drink, called "Ginger Jake," contained an adulterated Jamaican ginger extract containing tri-ortho-cresyl phosphate (TOCP) which resulted in partially reversible neurologic damage. The damage resulted in the limping "Jake Leg" or "Jake Walk" which were terms frequently used in the blues music of the period. Europe and Morocco both experienced outbreaks of TOCP poisoning from contaminated abortifacients and cooking oil, respectively.

Gulf War syndrome
Research has linked the neurological abnormalities found in Persian Gulf War veterans who have chronic multisymptom illnesses to exposure to wartime combinations of organophosphate chemical nerve agents. Before, it was believed that veterans had a psychologically based disorder or depression, most likely post-traumatic stress disorder (PTSD). Many veterans were given pyridostigmine bromide (PB) pills to protect against nerve gas agents such as sarin and soman. During the war veterans were exposed to combinations of organophosphate pesticides and nerve agents, which produced symptoms associated with chronic organophosphate-induced delayed polyneuropathy (OPIDP) syndrome. Similar symptoms found in the veterans were the same symptoms reported for individuals in occupational settings who were acutely poisoned by organophosphates, such as chlorpyrifos. Studies found veterans experienced deficits in intellectual and academic abilities, simple motor skills, memory impairment, and impaired emotional function. These symptoms indicate brain damage, not a psychologically based disorder.

Society and culture
United States
Under a 1988 amendment to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the U.S. Environmental Protection Agency (EPA) regulates organophosphate pesticides Its focus was initially on registering pesticides for use on food crops. No pesticide can be sold in the United States before the EPA has reviewed the manufacturers application for registration and determined that the use of the product will not present an unreasonable risk to the public or the environment. In 1996, with the passage of the Food Quality Protection Act, Congress required the EPA to reassess all existing pesticide tolerances with specific consideration for children. This resulted in a 10-year review process of the health and environmental effects of all pesticides, beginning with the organophosphates. As part of that process, in 1999 the EPA announced a ban the use of organophosphate pesticide methyl parathion and significant restrictions on the use of another OP, azinphos methyl, in what they called "kids food".   The review process was concluded in 2006 and eliminated or modified thousands of other uses of pesticides. Other legislative action has been taken to protect children from the risks of organophosphates.
Many non-governmental and research groups, as well as the EPAs Office of Inspector General, have expressed concerns that the review did not take into account possible neurotoxic effects on developing fetuses and children, an area of developing research. OIG report. A group of leading EPA scientists sent a letter to the chief administrator, Stephen Johnson, decrying the lack of developmental neurotoxicity data in the review process. EPA Letter EHP article New studies have shown toxicity to developing organisms during certain "critical periods" at doses much lower than those previously suspected to cause harm.Even the restrictions which did successfully pass have been controversial. For example, in 1999 the EPA restricted the use of chlorpyrifos in households (under the commercial name Dursban). However, the EPA did not limit its use in agriculture. Chlorpyrifos remains one of the most widely used pesticides. This may soon change. On February 8, 2013, the EPA requested comment on a preliminary evaluation of the potential risks to children and other bystanders from volatilization of chlorpyrifos from treated crops

Vulnerable groups
Some populations are more vulnerable to pesticide poisoning </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Retropharyngeal abscess and explain in detail? [/INST] Retropharyngeal abscess (RPA) is an abscess located in the tissues in the back of the throat behind the posterior pharyngeal wall (the retropharyngeal space).  Because RPAs typically occur in deep tissue, they are difficult to diagnose by physical examination alone. RPA is a relatively uncommon illness, and therefore may not receive early diagnosis in children presenting with stiff neck, malaise, difficulty swallowing, or other symptoms listed below. Early diagnosis is key, while a delay in diagnosis and treatment may lead to death. Parapharyngeal space communicates with retropharyngeal space and an infection of retropharyngeal space can pass down behind the esophagus into the mediastinum. RPAs can also occur in adults of any age.
RPA can lead to airway obstruction or sepsis – both life-threatening emergencies. Fatalities normally occur from patients not receiving treatment immediately and suffocating prior to knowing that anything serious was wrong.

Signs and symptoms
Signs and symptoms may include the following stiff neck (limited neck mobility or torticollis), some form of palpable neck pain (may be in "front of the neck" or around the Adams Apple), malaise, difficulty swallowing, fever, stridor, drooling, croup-like cough or enlarged cervical lymph nodes </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cryoglobulinemia and explain in detail? [/INST] Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called  cryoglobulins – proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.
Cryoglobulins typically precipitate (clumps together) at temperatures below normal body temperature – 37 degrees Celsius (99 degrees Fahrenheit) – and will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become gangrenous. While this disease is commonly referred to as cryoglobulinemia in the medical literature, it is better termed cryoglobulinemic disease for two reasons: 1) cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease and 2) healthy individuals can develop transient asymptomatic cryoglobulinemia following certain infections.In contrast to these benign instances of circulating cryoglobulins, cryoglobulinemic disease involves the signs and symptoms of precipitating cryoglobulins and is commonly associated with various pre-malignant, malignant, infectious, or autoimmune diseases that are the underlying cause for production of the cryoglobulins.

Classification
Since the first description of cryoglobulinemia in association with the clinical triad of skin purpura, joint pain, and weakness by Meltzer et al. in 1967, the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia, that is cryoglobulinemic disease that is unassociated with an underlying disorder, has fallen. Currently most cases of this disease are found to be associated with premalignant, malignant, infectious, or autoimmune disorders that are the known or presumed causes for the production of cryoglobulins. This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification. The classification distinguishes three subtypes of cryoglobulinemic diseases based on two factors, the class of immunoglobulins in the cryoglobulin and the association of the cryoglobulinemic disease with other disorder. The following table lists these three types of cryoglobulinemic disease, characterized on the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, percentage of total cryoglobulinemic disease cases, and class of disorders associated for each type.
The monoclonal or polyclonal IgM proteins involved in Types II and III cryoglobulinemic disease have rheumatoid factor activity. That is, they bind to polyclonal immunoglobulins, activate the blood complement system, and thereby form tissue deposits that contain IgM, IgG (or, rarely, IgA), and components of the complement system, including in particular complement component 4. The vascular deposition of these types of cryoglobulin-containing immune complexes and complement can cause a clinical syndrome of cutaneous small-vessel vasculitis characterized by systemic vasculitis and inflammation termed cryoglobulinemic vasculitis. Accordingly, type II and type III cryoglobulinemic diseases are often grouped together and referred to as mixed cryoglobulinemia or mixed cryoglobulinemic disease. The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity.More recent high resolution protein electrophoresis methods have detected a small monoclonal immunoglobulin component in type III cryoglobulins and/or a micro-heterogeneous composition of oligo-clonal (i.e., more than one monoclonal) immunoglobulin components or immunoglobulins with structures that do not fit into any classifications in the cryoglobulins of ≈10% of type II and III disease cases. It has been proposed that these cases be termed an intermediate type II-III variant of cryoglobulinemic disease and that some of the type III cases associated with the expression of low levels of a one or more isotypes of circulating monoclonal immunoglobulin(s) are in transition to type II disease.

Signs and symptoms
The clinical features of cryoglobulinemic disease can reflect those due not only to the circulation of cryoglobulins but also to any underlying hematological premalignant or malignant disorder, infectious disease, or autoimmune syndrome. The following sections of clinical features focuses on those attributed to the cryoglobulins. Cryoglobulins cause tissue damage by three mechanisms; they can:

a) increase blood viscosity thereby reducing blood flow to tissues to cause the hyperviscosity syndrome (i.e., headache, confusion, blurry or loss of vision, hearing loss, and epistaxis;
b) deposit in small arteries and capillaries thereby plugging these blood vessels and causing infarction and necrosis of tissues including in particular skin (e.g., ears), distal extremities, and kidneys;
c) in type II and type III disease, deposit on the endothelium of blood vessels and activate the blood complement system to form pro-inflammatory elements such as C5a thereby initiating the systemic vascular inflammatory reaction termed cryoglobulinemic vasculitis.

Essential cryoglobulinemic disease
The signs and symptoms in the increasingly rare cases of cryoglobulinemic disease that cannot be attributed to an underlying disease generally resemble those of patients suffering Type II and III (i.e., mixed) cryoglobulinemic disease.

Type I cryoglobulinemic disease
Signs and symptoms due to the cryoglobulins of type I disease reflect the hyperviscosity and deposition of cryoglobulins within the blood vessels which reduce or stop blood perfusion to tissues. These events occur particularly in cases where blood cryoglobulin levels of monoclonal IgM are high in patients with IgM MGUS, smoldering Waldenströms macroglobulinemia, or Waldenströms macroglobulinemia and in uncommon cases where the levels of monoclonal IgA, IgG, free κ light chains, or free λ light chains are extremely high in patients with non-IgM MGUS, non-IgM smoldering multiple myeloma, or multiple myeloma. The interruption of blood flow to neurological tissues can cause symptoms of confusion, headache, hearing loss, and peripheral neuropathy. Interruption of blood flow to other tissues in type I disease can cause cutaneous manifestations of purpura, blue discoloration of the arms or legs (acrocyanosis), necrosis, ulcers, and livedo reticularis; spontaneous nose bleeds, joint pain, membranoproliferative glomerulonephritis; and cardiovascular disturbances such as shortness of breath, inadequate levels of oxygen in the blood (hypoxemia), and congestive heart failure.

Types II and III cryoglobulinemic disease
Types II and III (or mixed or variant) cryoglobulinemic disease may also present with symptoms and signs of blood hyperviscosity syndrome and deposition of cryoglobulins within blood vessels but also include those attributable to cryoglobulinemic vasculitis. "Meltzers triad" of palpable purpura, joint pain, and generalized weakness occurs in ≈33% of patients presenting with type II or type III disease. One or more skin lesions including palpable purpura, ulcers, digital gangrene, and areas of necrosis occur in 69-89% of these mixed disease cases (see attached photograph); less common findings include painful peripheral neuropathy (often manifesting as mononeuritis multiplex in 19-44% of cases), kidney disease (primarily membranoproliferative glomerulonephritis (30%), joint pain (28%), and, less commonly, dry eye syndrome, Raynaud phenomenon (i.e., episodic painful reductions in blood flow to the fingers and toes). While the glomerulonephritis occurring in mixed disease appears to be due to inflammatory vasculitis, the glomerulonephritis occurring in type I disease appears due to the interruption of blood flow. The hematological, infectious, and autoimmune diseases underlying type II cryoglobulinemic disease and the infectious and autoimmune diseases underlying type III cryoglobulinemic disease are also critical parts of the diseases clinical findings.

Mechanism
Cryoglobulins
Cryoglobulins consists of one or more of the following components: monoclonal or polyclonal IgM, IgG, IgA antibodies, monoclonal  κ, or λ free light chain portions of these antibodies, and proteins of the blood complement system, particularly complement component 4 (C4). The particular components involved are a reflection of the disorders which are associated with, and considered to be the cause of, the cryoglobulinemic disease. The cryoglobulin compositions and disorder associations in cryoglobulinemic disease are as follows:

Monoclonal IgM-based cryoglobulin occurs in cases of Waldenströms macroglobulinemia and the pre-malignant precursors to this cancer, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenstroms macroglobulinemia.
Monoclonal IgG or, rarely, IgA, κ light chain, or λ light chain cryoglobulins occur in cases of multiple myeloma and the pre-malignant precursors to this cancer, non-IgM monoclonal gammopathy of undetermined significance and non-IgM smoldering multiple myeloma. Non-IgM monoclonal immunoglobulin-based cases of cryoglobulinemic disease are less commonly associated with other B-cell lymphocytic diseases viz., Non-Hodgkin lymphoma, Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and Castleman disease; they occur rarely in non-B cell hematological disorders such as myelodysplastic syndromes and chronic myelogenous leukemia. Among these purely monoclonal immunoglobulin causes of cryoglobulinemic disease, Waldenström macroglobulinemia and multiple myeloma together account for ≈40% of cases; their pre-malignant precursors account for ≈44% of cases; and the other cited hematological diseases account for ≈16% of cases.
Mixtures of monoclonal or polyclonal IgM, IgG, and/or IgA along with blood complement proteins such as C4 are the cryoglobulins associated with cases of infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection, and, less commonly or rarely, with cases of other infectious diseases such as hepatitis B infection, hepatitis A infection, cytomegalovirus infection, Epstein–Barr virus infection, Lyme disease, syphilis, lepromatous leprosy, Q fever, poststreptococcal nephritis, subacute bacterial endocarditis, coccidioidomycosis, malaria, schistosomiasis, echinococcosis, toxoplasmosis, and Kala-azar. These mixed-protein cryoglobulins are also associated with autoimmune diseases, particularly Sjögren syndrome, less commonly systemic lupus erythematosus and rheumatoid arthritis, and rarely polyarteritis nodosa, systemic sclerosis,  temporal arteritis, polymyositis, Henoch–Schönlein purpura, pemphigus vulgaris, sarcoidosis, inflammatory bowel diseases, and others. In these mixed-protein depositions, the monoclonal or polyclonal IgM typically possesses rheumatoid factor activity and therefore binds to the Fc region of polyclonal IgG antibodies, activates the blood complement system, and complexes with complement components to form precipitates composed of IgM, IgG or IgG, and complement components, particularly complement component 4 (C4).

Diagnosis
Cryoglobulinemia and cryoglobulinemic disease must be distinguished from cryofibrinogenemia or cryofibrinogenemic disease, conditions which involve the cold-induced intravascular deposition of circulating native fibrinogens. These molecules precipitate at lower temperatures (e.g., 4 °C). Since cryofibrinogens are present in plasma but greatly depleted in serum, precipitation tests for them are positive in plasma but negative in serum. Cryofibrinogenemia is occasionally found in cases of cryoglobulinemic disease. Cryoglobulinemic disease must also be distinguished from frostbite as well as numerous other conditions that have a clinical (particularly cutaneous) presentation similar to cryoglobulinemic disease but are not exacerbated by cold temperature, e.g., dysfibrinogenemia and dysfibrinogenemic disease (conditions involving the intravascular deposition of genetically abnormal circulating fibrinogens), purpura fulminans, cholesterol emboli, warfarin necrosis, ecthyma gangrenosum, and various hypercoagulable states.Rheumatoid factor is a sensitive test for cryoglobulinemia. The precipitated cryoglobulins are examined by immunoelectrophoresis and immunofixation to detect and quantify the presence of monoclonal IgG, IgM, IgA, κ light chain, or λ light chain immunoglobins. Other routine tests include measuring blood levels of rheumatoid factor activity, complement C4, other complement components, and hepatitic C antigen. Biopsies of skin lesions and, where indicated, kidney or other tissues can help in determining the nature of the vascular disease (immunoglobulin deposition, cryoglobulinemic vasculitis, or, in cases showing the presence of cryfibrinogenemia, fibrinogen deposition. In all events, further studies to determine the presence of hematological, infections, and autoimmune disorders are conducted on the basis of these findings as well as each cases clinical findings.

Treatment
All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.

Asymptomatic cryoglobulinemia
Individuals found to have circulating cryoglobulins but no signs or symptoms of cryoglobulinemic diseases should be evaluated for the possibility that their cryoglobulinemia is a transient response to a recent or resolving infection. Those with a history of recent infection that also have a spontaneous and full resolution of their cryoglobulinemia need no further treatment. Individuals without a history of infection and not showing resolution of their cryoglobulinemia need to be further evaluated. Their cryoglobulins should be analyzed for their composition of immunoglobulin type(s) and complement component(s) and examined for the presence of the premalignant and malignant diseases associated with Type I disease as well as the infectious and autoimmune diseases associated with type II and type III disease. A study conducted in Italy on >140 asymptomatic individuals found five cases of hepatitis C-related and one case of hepatitis b-related cryoglobulinemia indicating that a complete clinical examination of asymptomatic individuals with cryoglobulinemia offers a means for finding people with serious but potentially treatable and even curable diseases. Individuals who show no evidence of a disease underlying their cryoglobulinemia and who remain asymptomatic should be followed closely for any changes that may indicate development of cryoglobulinemic disease.

Severely symptomatic cryoglobulinemic disease
People affected by the severest, often life-threatening, complications of cryoglobulinemic disease require urgent plasmapharesis and/or plasma exchange in order to rapidly reduce the circulating levels of their cryoglobulins </s>